Novel piperidine compound

ABSTRACT

The present invention provides a novel piperidine compound of the formula [I]: wherein Ring A represents an optionally substituted benzene ring, Ring B represents an optionally substituted benzene ring, R 1  represents an optionally substituted alkyl group, an optionally substituted hydroxyl group, etc., or a group of the formula: (a) wherein R 11  and R 12  are the same or different, and each represents hydrogen atom, a substituted carbonyl group, a substituted sulfonyl group, an optionally substituted alkyl group, etc., R 2  represents hydrogen atom, etc., Z represents oxygen atom or a group represented by —N(R 3 )—, R 3  represents hydrogen atom or an alkyl group, etc., R 4  represents hydrogen atom or an alkyl group, etc., or a pharmaceutically acceptable salt thereof.

TECHNICAL FIELD

The present invention relates to a novel piperidine compound havingexcellent tachykinin receptor antagonistic action.

BACKGROUND ART

Tachykinin is a general name for a group of neuropeptides, and therehave been known substance P (hereinafter referred to as SP),neurokinin-A, and neurokinin-B in mammals. These peptides are known toexhibit a various kinds of biological activities by binding theircorresponding receptors which exist in vivo (neurokinin-1, neurokinin-2,neurokinin-3). Among them, SP is one of those which have the longesthistory in the neuropeptides, and have been studied in detail. Itsexistence was confirmed in an extract of horse intestinal tube in 1931,and it was a peptide comprising 11 amino acids, whose structure wasdetermined in 1971.

SP exists widely in peripheral nervous system, and it has physiologicalactivities such as vasodilation action, vascular permeability promotingaction, smooth muscle contracting action, hypertarachia (neuronalexcitement) action, salivation action, diuretic action, immunologicalaction, etc., as well as a function of neurotransmitter of the primarysensory neuron. Specifically, it is known that SP released from theterminus of posterior horn of spinal cord upon pain impulse transferspain information to the secondary neuron, and that SP released from theperipheral terminus induces an inflammatory reaction in the receptor.From these facts, SP is considered to be involved in various diseases(for example, pain, inflammation, allergy, thamuria, incontinence ofurine, respiratory disease, mental illness, depression, uneasiness,emesis, etc.), and also, SP is considered to be involved in Alzheimertype dementia [Review: Physiological Reviews, vol. 73, pp. 229-308(1993), Journal of Autonomic Pharmacology, vol. 13, pp. 23-93 (1993)].

Currently, as a therapeutic agent for the above-mentioned variousdiseases (especially for emesis, depression, urination disorder, etc.),there have not been discovered yet any compound having an excellenttachykinin receptor antagonistic action (specifically, SP receptorantagonistic action), and at the same time, having sufficientlysatisfying safety, sustainability (metabolism, dynamics in vivo, andabsorption), etc. Therefore, a compound has been sought for which has anexcellent tachykinin receptor antagonistic action, and has sufficientlysatisfying clinical effect as the therapeutic agent.

Accordingly, an object of the present invention is to provide a compoundhaving excellent tachykinin receptor antagonistic action, and having aclinical satisfying effect in terms of safety, sustainability(metabolism, dynamics in vivo and absorption), etc.

SUMMARY OF THE INVENTION

The present invention relates to a piperidine compound represented bythe formula [I]:

-   -   wherein Ring A represents an optionally substituted benzene        ring, Ring B represents an optionally substituted benzene ring,        R¹ represents an optionally substituted alkyl group, an        optionally substituted hydroxyl group, a substituted thiol        group, a substituted carbonyl group, a substituted sulfinyl        group, a substituted sulfonyl group, or a group represented by        the formula:    -   wherein R¹¹ and R¹² are the same or different and each is        hydrogen atom, a substituted carbonyl group, a substituted        sulfonyl group, an optionally substituted alkyl group or a        heterocyclic group containing 1 to 4 atom(s) selected from        nitrogen atom, oxygen atom and sulfur atom as a hetero atom,        wherein the heterocyclic group is optionally substituted, and        the nitrogen atom contained in the heterocyclic group is        optionally oxidized, or R¹¹ and R¹² are taken together, with an        adjacent nitrogen atom, to form a heterocyclic group selected        from piperidino group, azacycloheptyl group, pyrrolidino group,        imidazolidinyl group, hexahydropyrimidinyl group, thiazolidyl        group, morpholino group, triazolyl group, tetrazolyl group and        purinyl group, wherein the heterocyclic group is optionally        substituted, and the nitrogen atom contained in the heterocyclic        group is optionally oxidized, R² represents hydrogen atom, an        optionally substituted hydroxyl group, an optionally substituted        amino group, an optionally substituted alkyl group, a        substituted carbonyl group or a halogen atom, Z represents        oxygen atom or a group represented by —N(R³)—, wherein R³        represents hydrogen atom or an optionally substituted alkyl        group, R⁴ represents hydrogen atom or an optionally substituted        alkyl group,        or a pharmaceutically acceptable salt thereof.

In the present invention, Ring A represents an optionally substitutedbenzene ring, and a substituent of the benzene ring is exemplified by analkyl group, a halogen atom, cyano group, optionally protected hydroxylor alkoxy group. Ring A may have 1 to 3 of these substituent(s) which is(are) the same or different.

In the present invention, Ring B represents an optionally substitutedbenzene ring, and a substituent of the benzene ring is exemplified by atrihalogenoalkyl group, a halogen atom, a cyano group, a phenyl group, aheterocyclic group containing 1 to 4 atom(s) selected from nitrogenatom, oxygen atom and sulfur atom as hetero atom, an alkyl group, anoptionally protected hydroxyl or an alkoxy group. Ring B may have 1 to 3of these substituent(s) which are the same or different.

A preferred example of Ring A and Ring B in the compound of the presentinvention is exemplified by a compound wherein Ring A is a benzene ringof the formula:

and Ring B is a benzene ring of the formula:

-   -   wherein A¹, A² and A³ are the same or different, and each is        hydrogen atom, a halogen atom, an alkyl group, an optionally        protected hydroxyl or alkoxy group,    -   B¹, B²and B³ are the same or different, and each is hydrogen        atom, a trihalogenoalkyl group, a halogen atom, a cyano group, a        phenyl group, a heterocyclic group containing 1 to 4 atom(s)        selected from nitrogen atom, oxygen atom and sulfur atom as        hetero atom, an alkyl group, an optionally protected hydroxyl or        an alkoxy group. The trihalogenoalkyl group is exemplified by a        trifluoromethyl group or a trichloromethyl group, etc. The        heterocyclic group is exemplified by a tetrazolyl group, etc.

In the present invention, a protecting group of the optionally protectedhydroxyl group is exemplified by a conventional protection group such asan optionally substituted arylalkyl group, an optionally substitutedsilyl group and an acyl group. In the above, preferred are an arylalkylgroup such as benzyl group and phenethyl group, a substituted silylgroup such as tert-butyldimethylsilyl group and tert-butyldiphenylsilylgroup, and an acyl group such as formyl group, acetyl group, propionylgroup, malonyl group, acryloyl group and benzoyl group.

In the present invention, R¹ is an optionally substituted alkyl group,an optionally substituted hydroxyl group, a substituted thiol group, asubstituted carbonyl group, a substituted sulfinyl group, a substitutedsulfonyl group, or a group represented by the formula:

-   -   wherein R^(11 and R) ¹² are the same or different, and each is        hydrogen atom , a substituted carbonyl group, a substituted        sulfonyl group, an optionally substituted alkyl group or a        heterocyclic group containing 1 to 4 atom(s) selected from        nitrogen atom, oxygen atom and sulfur atom as a hetero atom,        wherein the heterocyclic group is optionally substituted, and        the nitrogen atom contained in the heterocyclic group is        optionally oxidized, or R¹¹ and R¹² are taken together, with an        adjacent nitrogen atom, to form a heterocyclic group selected        from piperidino group, azacycloheptyl group, pyrrolidino group,        imidazolidinyl group, hexahydropyrimidinyl group, thiazolidyl        group, morpholino group, triazolyl group, tetrazolyl group and        purinyl group, wherein the heterocyclic group is optionally        substituted, and the nitrogen atom contained in the heterocyclic        group is optionally oxidized.

In the above, R¹ is preferably an optionally substituted alkyl group, anoptionally substituted hydroxyl group, a substituted thiol group, asubstituted carbonyl group, a substituted sulfinyl group, a substitutedsulfonyl group, or a group represented by the formula:

wherein R¹¹ and R¹² are the same or different, and each is hydrogenatom, a substituted carbonyl group, a substituted sulfonyl group, anoptionally substituted alkyl group or a heterocyclic group containing 1to 4 atom(s) selected from nitrogen atom, oxygen atom and sulfur atom asa hetero atom, wherein the heterocyclic group is optionally substituted,and the nitrogen atom contained in the heterocyclic group is optionallyoxidized,further preferably is an optionally substituted alkyl group, anoptionally substituted hydroxyl group, a substituted thiol group, asubstituted carbonyl group, a substituted sulfinyl group, a substitutedsulfonyl group, or a group represented by the formula:

-   -   wherein R¹¹ is a substituted carbonyl group, a substituted        sulfonyl group or a heterocyclic group containing 1 to 4 atom(s)        selected from nitrogen atom, oxygen atom and sulfur atom as a        hetero atom, wherein the heterocyclic group is optionally        substituted, and the nitrogen atom contained in the heterocyclic        group is optionally oxidized, and R¹² is hydrogen atom, an        optionally substituted alkyl group, a substituted carbonyl        group, a substituted sulfonyl group or a heterocyclic group        containing 1 to 4 atom(s) selected from nitrogen atom, oxygen        atom and sulfur atom as a hetero atom, wherein the heterocyclic        group is optionally substituted, and the nitrogen atom contained        in the heterocyclic group is optionally oxidized.

In the present invention, the substituent of the optionally substitutedalkyl group of R¹ is exemplified by an alkoxycarbonyl group, amorpholinocarbonyl group, a pyridylaminocarbonyl group, amorpholinoaminocarbonyl group, a piperidinocarbonyl group substituted byan alkoxyphenyl group, a dialkylaminocarbonyl group, hydroxyl group, ahydroxyalkylaminocarbonyloxy group or an alkylpiperazinocarbonyl group.

In the present invention, the substituent of the optionally substitutedhydroxyl group of R¹ is exemplified by

-   -   (1) a substituted carbonyl group,    -   (2) a substituted sulfinyl group,    -   (3) a substituted sulfonyl group or    -   (4) an optionally substituted alkyl group.

The substituent of the substituted carbonyl group in the above (1) isexemplified by an optionally substituted alkyl group, an optionallysubstituted alkoxy group, a substituted amino group, a monocyclicheterocyclic group having 1 to 2 atom(s) selected from nitrogen atom andoxygen atom as a hetero atom (the monocyclic heterocyclic group isoptionally substituted). The substituent of the optionally substitutedalkyl group is exemplified by hydroxyl group. The substituent of theoptionally substituted alkoxy group is exemplified by an alkoxy group,hydroxyl group or a halogen atom. The substituent of the substitutedamino group is exemplified by an alkyl group substituted by a groupselected from a halogen atom, a dialkylamino group, piperidinyl group,morpholino group, a carboxyl group, a morpholinocarbonyl group, adialkylaminocarbonyl group, an alkylaminocarbonyl group, analkanoylamino group, an alkylthio group, an alkoxy group, analkylsulfonyl group, an alkanoyloxy group and hydroxyl group;piperidinyl group substituted by a hydroxyalkanoyl group or analkoxyalkanoyl group; or a dialkylamionsulfonyl group. The monocyclicheterocyclic group is exemplified by morpholino group, piperazinylgroup, imidazolyl group, thiomorpholino group, piperidino group, furylgroup, tetrahydrothiazolinyl group or pirrolidinyl group. Thesubstituent of the monocyclic heterocyclic group is exemplified by analkyl group which may be substituted by hydroxyl group, analkoxycarbonyl group, a carboxyl group, hydroxyalkylaminocarbonyl group,alkoxyalkylaminocarbonyl group, alkylthioalkylaminocarbonyl group,alkylsulfinylalkylaminocarbonyl group, analkylsulfonylalkylaminocarbonyl group or morpholino group, an oxo groupor hydroxyl group.

The substituent of the substituted sulfinyl group in the above (2) isexemplified by an alkyl group or thienyl group.

The substituent of the substituted sulfonyl group in the above (3) isexemplified by an alkyl group or thienyl group.

The substituent of the optionally substituted alkyl group in the above(4) is exemplified by an optionally substituted hydroxyl group, adialkylamino group or a monocyclic heterocyclic group having 1 to 4atom(s) selected from sulfur atom, nitrogen atom and oxygen atom as ahetero atom (the monocyclic heterocyclic group is optionallysubstituted). The substituent of the optionally substituted hydroxylgroup is exemplified by an alkyl group, an alkylsulfonyl group ortetrahydropyranyl group. The monocyclic heterocyclic group isexemplified by pyridyl group, piperidinyl group, morpholino group,isoxazolyl group, triazolyl group, tetrazolyl group or pirrolidinylgroup. The substituent of the monocyclic heterocyclic group isexemplified by an alkyl group or a phenyl group.

In the present invention, the substituent of the substituted thiol groupof R¹ is exemplified by a substituted phenyl group, a substitutedcarbonyl group or an optionally substituted alkyl group. The substituentof the substituted phenyl group is exemplified by hydroxyl group. Thesubstituent of a substituted carbonyl group is exemplified by an alkylgroup. The substituent of the optionally substituted alkyl group isexemplified by an alkylaminocarbonyl group, a dialkylaminocarbonyl groupan alkoxycarbonylamino group, hydroxyalkanoylamino group, amorpholinocarbonylamino group, a hydroxyalkylaminocarbonylamino group,an alkanoyloxy group or hydroxyl group.

In the present invention, the substituent of the substituted carbonylgroup of R¹ is exemplified by hydroxyl group, an alkoxy group, anoptionally substituted amino group or a monocyclic heterocyclic grouphaving 1 to 4 atom(s), selected from sulfur atom, nitrogen atom andoxygen atom as a hetero atom(s) (the monocyclic heterocyclic group isoptionally substituted). The substituent of the optionally substitutedamino group is exemplified by (a) group(s) selected from pyridyl groupoptionally substituted by hydroxyl group(s), pyrimidyl group, analkylpyrido group, pyrazinyl group, and an alkyl group optionallysubstituted by hydroxyl group or cyano group. The monocyclicheterocyclic group is exemplified by piperidino group, piperazino group,morpholino group, thiomorpholino group or pyrrolidino group. Thesubstituent of the monocyclic heterocyclic group is exemplified by analkyl group, hydroxyl group, an oxo group, pyrimidyl group, pyrazinylgroup, an alkylsulfonyl group, an alkanoyl group or hydroxyalkyl group.

In the present invention, the substituent of the substituted sulfinylgroup of R¹ is exemplified by hydroxyl group or an optionallysubstituted alkyl group. The substituent of the optionally substitutedalkyl group is exemplified by hydroxyl group.

In the present invention, the substituent of the substituted sulfonylgroup of R¹ is exemplified by an optionally substituted alkyl group. Thesubstituent of the optionally substituted alkyl group is exemplified byhydroxyl group or an alkanoyloxy group.

In the present invention, when R¹ is a group of the formula:

-   -   (1) the substituent of the substituted carbonyl of R¹¹ and R¹²        is exemplified by an optionally substituted alkyl group, an        optionally substituted alkoxy group, an optionally substituted        aryl group, a substituted amino group or a heterocyclic group        containing 1 to 4 atom(s) selected from nitrogen atom, oxygen        atom and sulfur atom as a hetero atom, wherein the heterocyclic        group is optionally substituted, and the nitrogen atom contained        in the heterocyclic group is optionally oxidized. The        substituent of the optionally substituted alkyl group is        exemplified by an alkylaminocarbonyl group, a        dialkylaminocarbonyl group wherein the alkyl moiety thereof is        optionally substituted by hydroxyl group, an aminocarbonyl        group, an alkoxycarbonylamino group, an alkanoylamino group, an        amino group substituted by an alkoxycarbonyl group and an alkyl        group, an amino group substituted by an alkanoyl group and an        alkyl group, an alkoxy group, a halogen atom, tetrazolyl group,        pyridyl group, furyl group, hydroxyl group, an alkylthio group,        2-oxopyrrolidino group, 2-aminothiazolyl group,        2-thiol-4-akylthiazolyl group, 2,2-dialkyl-1,3-dioxolanyl group,        a cycloalkyl group, an alkylsulfinyl group, an alkylsulfonyl        group, thienyl group, 5-methyl-2,4(1H,3H)pyrimidinedione group,        an amino group or a dialkylamino group. The substituent of the        optionally substituted aryl group is exemplified by nitro group        or an amino group, and the aryl group is exemplified by phenyl        group, naphthyl group, phenanthryl group or anthracenyl group.        The substituent of the substituted amino group is exemplified by        an alkyl group optionally substituted by a group selected from a        halogen atom, an alkoxy group and hydroxyl group, and the amino        group is mono-substituted or di-substituted. The heterocyclic        group is exemplified by a saturated or unsaturated monocyclic or        bicyclic aromatic heterocyclic group, such as thienyl group,        furyl group, tetrahydrofuryl group, pyranyl group, pyrrolyl        group, imidazolyl group, pyrazolyl group, isothiazolyl group,        isoxazolyl group, pyridyl group, pyrazinyl group, pyrimidinyl        group, pyridazinyl group, pirrolidinyl group, pyrrolinyl group,        imidazolidinyl group, imidazolinyl group, pyrazolidinyl group,        pyrazolinyl group, piperidyl group, piperazinyl group,        morpholinyl group, thiomorpholinyl group, benzothienyl group,        benzofuryl group, isobenzofuranyl group, chromenyl group,        indolyl group, isoindolyl group, indazolyl group, purinyl group,        quinolizinyl group, naphthyridinyl group, quinoxalinyl group,        cinnolinyl group, quinolyl group, isoquinolyl group,        benzothiazolyl group, benzisothiazolyl group, quinazolinyl        group, phthalazinyl group, benzoxazolyl group, benzimidazolyl        group, pteridinyl group, pyridopyrimidinyl group, isochromanyl        group, chromanyl group, indolinyl group, isoindolinyl group,        tetrahydroquinolyl group, tetrahydroisoquinolyl group,        tetrahydroquinoxalinyl group, dihydrophthalazinyl group, etc.        Among these heterocyclic groups, pyridyl group, pirrolidinyl        group, piperazinyl group, quinolyl group, piperidinyl group,        pyrimidyl group, thiazolyl group, pyrazinyl group, morpholino        group, thiomorpholino group, indolyl group, cinnolinyl group,        furyl group, tetrahydrofuryl group, thienyl group, etc. are        preferably used. The substituent of the heterocyclic group is        exemplified by a dialkylamino group, an alkoxycarbonyl group,        morpholinoalkyl group, a hydroxyalkyl group, an alkyl group,        benzyloxy group, an alkoxycarbonyl group, an alkanoyl group,        hydroxyl group, an oxo group or formyl group.    -   (2) The substituent of the substituted sulfonyl group of R¹¹ and        R¹² is exemplified by an optionally substituted alkyl group,        cyanophenyl group, a dialkylamino group, or alkenyl group. The        substituent of the the optionally substituted alkyl group is        exemplified by a halogen atom, hydroxyl group, a dialkylamino        group optionally substituted by hydroxyl group, morpholino        group, piperidino group or 4-methylpiperazino group.    -   (3) The substitutent of the optionally substituted alkyl group        of R¹¹ and R¹² is exemplified by a dialkylaminocarbonyl group,        an alkoxy group, a dialkylamino group, cyano group, morpholino        group, pyridyl group or a halogen atom.    -   (4) The heterocyclic group containing 1 to 4 atom(s) selected        from nitrogen atom, oxygen atom and sulfur atom as a hetero atom        of R¹¹ and R¹² is exemplified by a saturated or unsaturated        monocyclic or bicyclic aromatic heterocyclic group, such as        thienyl group, furyl group, pyranyl group, pyrrolyl group,        imidazolyl group, pyrazolyl group, isothiazolyl group,        isoxazolyl group, pyridyl group, pyrazinyl group, pyrimidinyl        group, pyridazinyl group, pirrolidinyl group, pyrrolinyl group,        imidazolidinyl group, imidazolinyl group, pyrazolidinyl group,        pyrazolinyl group, piperidyl group, piperazinyl group,        morpholinyl group, benzothienyl group, benzofuryl group,        isobenzofuranyl group, chromenyl group, indolyl group,        isoindolyl group, indazolyl group, purinyl group, quinolizinyl        group, naphthyridinyl group, quinoxalinyl group, cinnolinyl        group, quinolyl group, isoquinolyl group, benzothiazolyl group,        benzisothiazolyl group, quinazolinyl group, phthalazinyl group,        benzoxazolyl group, benzimidazolyl group, pteridinyl group,        pyridopyrimidinyl group, isochromanyl group, chromanyl group,        indolinyl group, isoindolinyl group, tetrahydroquinolyl group,        tetrahydroisoquinolyl group, tetrahydroquinoxalinyl group,        dihydrophthalazinyl group. Of these heterocyclic groups, pyridyl        group, pyrrolyl group, piperazinyl group, quinolyl group,        piperidinyl group, pyrimidyl group, thiazolyl group, pyrazinyl        group, morpholino group, indolyl group, cinnolinyl group, furyl        group, thienyl group, etc. are preferably used. The substituent        of the heterocyclic group is exemplified by a dialkylamino        group, an alkoxycarbonyl group, an alkyl group, an alkoxy group,        hydroxyl group, a halogen atom etc.

Further, when R¹¹ and R¹² form a bond at the termini thereof, to form aheterocyclic group, with an adjacent nitrogen atom, selected frompiperidino group, azacycloheptyl group, pyrrolidino group,imidazolidinyl group, hexahydropyrimidinyl group, thiazolidyl group,morpholino group, triazolyl group, tetrazolyl group and purinyl group,the substituent of the heterocyclic group is exemplified by an alkylgroup substituted by an alkoxy group or hydroxyl group, piperidinylgroup, alkoxyphenyl group, an alkanoyl group, hydroxyl group, an oxogroup and an amino group.

When the nitrogenatom of the heterocyclic group is oxidized, theoxidized nitrogen atom means a state where the nitrogen atom iscationized, which is exemplified by N-oxomorpholino group orN-alkylmorpholinio group.

In the present invention, R² represents hydrogen atom, an optionallysubstituted hydroxyl group, an optionally substituted amino group, anoptionally substituted alkyl group, a substituted carbonyl group or ahalogen atom.

In the present invention, the substituent of the optionally substitutedhydroxyl group of R² is exemplified by an alkyl group.

In the present invention, the substituent of the optionally substitutedamino group of R² is exemplified by an alkyl group.

In the present invention, the substituent of the optionally substitutedalkyl group of R² is exemplified by an alkoxy group.

In the present invention, the substituent of the substituted carbonylgroup of R² is exemplified by hydroxyl group, an alkoxy group oralkylamino group.

In the present invention, Z is exemplified by an oxygen atom or a groupof —N(R³)—.

In the present invention, R³ is exemplified by hydrogen atom or anoptionally substituted alkyl group. The substituent of the optionallysubstituted alkyl group of R³ is exemplified by hydroxyl group, analkanoyl group, a halogen atom, an alkoxy group or an alkylamino group.

In the present invention, R⁴ is exemplified by hydrogen atom or anoptionally substituted alkyl group. The substituent of the optionallysubstituted alkyl group of R⁴ is exemplified by a halogen atom, analkoxy group or alkylamino group.

As the preferred compound of the present invention, a compound where R¹is an optionally substituted alkyl group is mentioned.

The preferred substituent of the optionally substituted alkyl group isdialkylaminocarbonyl group, morpholinocarbonyl group, hydroxyl group,alkoxycarbonyl group or hydroxyalkylaminocarbonyloxy group.

As the preferred compound of the present invention, a compound where R¹is an optionally substituted hydroxyl group is mentioned. Of these,preferred is a compound where R¹ is an optionally substituted alkoxygroup. Additionally preferred is a compound where R¹ is an optionallysubstituted carbonyloxy group.

The preferred substituent of the optionally substituted alkoxy group ishydroxyl group, an alkylsulfonyloxy group, tetrahydropyranyloxy group, atriazolyl group, tetrazolyl group optionally substituted by alkyl group,or alkoxy group, and more preferred is hydroxyl group ortetrahydropyranyloxy group. The preferred substituent of the optionallysubstituted carbonyoxy group is morpholino group; imidazolyl group, analkylamino group wherein the alkyl moiety thereof is optionallysubstituted by hydroxyl group, morpholinocarbonyl group, adialkylaminocarbonyl group, an alkylaminocarbonyl group, alkanoylaminogroup, an alkylthio group, an alkoxy group, an alkylsulfonyl group, analkanoyloxy group or carboxyl group; piperidino group substituted byhydroxyl group, an alkoxycarbonyl group, carboxyl group, ahydroxyalkylaminocarbonyl group, an alkoxyalkylaminocarbonyl group, analkylthioalkylaminocarbonyl group, an alkylsulfinylalkylaminocarbonylgroup, an alkylsulfonylalkylaminocarbonyl group or a hydroxyalkyl group;piperidinylamino group substituted by a hydroxyalkanoyl group or analkoxyalkanoyl group; thiomorphorino group wherein the sulfur atom isoptionally substituted by oxo group; oxopyrroridinyl group;oxotetrahydrothiazolinyl group; or dialkylaminosulfonylamino group, andmore preferred is morpholino group; alkylamino group wherein the alkylmoiety thereof is optionally substituted by hydroxyl group; orthiomorpholino group wherein the sulfur atom is substituted by oxogroup.

As the preferred compound of the present invention, a compound where R¹is a substituted thiol group is mentioned.

The preferred substituent of the optionally substituted thiol group isan alkanoyl group; or an alkyl group optionally substituted by hydroxylgroup, an alkylaminocarbonyl group, a dialkylaminocarbonyl group, analkoxycarbonylamino group, a hydroxyalkanoylamino group,morpholinocarbonylamino group, a hydroxyalkylaminocarbonylamino group oran alkanoyloxy group.

As the preferred compound of the present invention, a compound where R¹is a substituted carbonyl group is mentioned.

The preferred substituent of the optionally substituted carbonyl groupis an alkoxy group; amino group optionally substituted by pyrimidylgroup or an alkylpyrido group; an alkylamino group wherein the alkylmoiety thereof is optionally substituted by hydroxyl group or cyanogroup; a di(hydroxyalkyl)amino group; a pyridylamino group wherein thepyridyl moiety thereof is optionally substituted by hydroxyl group;piperidino group substituted by hydroxy group or oxo group; piperazinogroup substituted by oxo group, an alkyl group, an alkylsulfonyl groupor alkanoyl group; morpholino group; thiomorpholino group; orpyrrolidino group substituted by an hydroxyalkyl group or hydroxylgroup, and more preferred is pyrimidylamino group or hydroxypiperazinogroup.

As the preferred compound of the present invention, a compound where R¹is a substituted sulfinyl group is mentioned.

The preferred substituent of the optionally substituted sulfinyl groupis an alkyl group optionally substituted by hydroxyl group, or hydroxylgroup, and more preferred is an alkyl group optionally substituted byhydroxyl group.

As the preferred compound of the present invention, a compound where R¹is a substituted sulfonyl group is mentioned.

The preferred substituent of the optionally substituted sulfonyl groupis an alkyl group optionally substituted by hydroxyl group or analkanoyloxy group, and more preferred is an alkyl group optionallysubstituted by hydroxyl group.

As the preferred compound of the present invention, a compound where R¹is the group of the formula:

-   -   wherein R¹¹ and R¹² are the same or different and each is        hydrogen atom, a substituted carbonyl group, a substituted        sulfonyl group, an optionally substituted alkyl group or a        heterocyclic group containing 1 to 4 atom(s) selected from        nitrogen atom, oxygen atom and sulfur atom as a hetero atom,        wherein the heterocyclic group is optionally substituted, and        the nitrogen atom contained in the heterocyclic group is        optionally oxidized, or R¹¹ and R¹² are taken together, with an        adjacent nitrogen atom, to form a heterocyclic group selected        from piperidino group, azacycloheptyl group, pyrrolidino group,        imidazolidinyl group, hexahydropyrimidinyl group, thiazolidyl        group, morpholino group, triazolyl group, tetrazolyl group and        purinyl group, wherein the heterocyclic group is optionally        substituted, and the nitrogen atom contained in the heterocyclic        group is optionally oxidized,        is mentioned.

Of these, preferred is a compound wherein R¹¹ is a substituted carbonylgroup and R¹² is hydrogen atom or an alkyl group. Further, each of thecompounds wherein R¹¹ is respectively, an optionally substitutedalkanoyl group, an optionally substituted aminocarbonyl group,morpholinocarbonyl group, and piperidinylcarbonyl group substituted byan alkanoyl group is respectively preferred. Another preferred exampleis a compound wherein R¹¹ is a substituted sulfonyl group and R¹² ishydrogen atom or an alkyl group.

The preferred substituent of the optionally substituted alkanoyl groupis an an alkanoyl group, an alkylaminocarbonyl group, adialkylaminocarbonyl group, aminocarbonyl group, an alkoxycarbonylaminogroup, an alkanoylamino group, amino group substituted by analkoxycarbonyl group and an alkyl group, amino group substituted by analkanoyl group and alkyl group, an alkoxy group optionally substitutedby phenyl group, furyl group, tetrazolyl group, hydroxyl group, analkylthio group, an alkylsulfinyl group, an alkylsulfonyl group,2-aminothiazolyl group, 2-oxopyrrolidino group,2-thiol-4-alkylthiazolydinyl group or a cycloalkyl group, and morepreferred is an alkoxy group, hydroxyl group or an cycloalkyl group. Thepreferred substituent of the optionally substituted aminocarbonyl groupis halogen atom, hydroxyl group or an alkyl group optionally substitutedby alkoxy group, and more preferred is an alkyl group. The preferredsubstituent of the optionally substituted sulfonyl group is an alkylgroup optionally substituted by hydroxyl group or halogen group, analkenyl group or a dialkylamino group, and more preferred is an alkylgroup.

The compound of the present invention is exemplified by a compound ofthe formula [I] wherein Ring A is a benzene ring of the formula:

and Ring B is a benzene ring of the formula:

-   -   wherein A¹ is an alkyl group, hydrogen atom, a halogen atom or        an alkoxy group, A² is hydrogen atom or a halogen atom, A³ is        hydrogen atom , B¹ is a trihalogenoalkyl group, a halogen atom        or an alkyl group, B² is a trihalogenoalkyl group, a halogen        atom or an alkyl group, B³ is hydrogen atom,    -   R¹ is hydroxyl group; an alkyl group substituted by a        dialkylaminocarbonyl group, a morpholinocarbonyl group, hydroxyl        group, an alkoxycarbonyl group, a morpholinoaminocarbonyl group,        a hydroxyalkylaminocarbonyloxy group or an        alkylpiperazinocarbonyl group; dihydroxyphenylthio group;        alkanoylthio group; an alkylthio group optionally substituted by        hydroxyl group, an alkylaminocarbonyl group, a        dialkylaminocarbonyl group, an alkoxycarbonylamino group,        hydroxyalkanoylamino group, a morpholinocarbonylamino group, a        hydroxyalkylaminocarbonylamino group or an alkanoyloxy group;        dialkylthionium group; an alkoxy group optionally substituted by        hydroxyl group, an alkylsulfonyloxy group, a        tetrahydropyranyloxy group, a dialkylamino group, pyridyl group,        a triazolyl group, a tetrazolyl group optionally substituted by        an alkyl group, piperidino group, morpholino group, pyrrolidino        group or an alkoxy group; thienylsulfonyloxy group;        morpholinocarbonyloxy group; alkyl piperazinocarbonyloxy group;        imidazolylcarbonyloxy group; piperidinoalkylaminocarbonyloxy        group; morpholinoalkylaminocarbonyloxy group; an        alkylaminocarbonyloxy group wherein the alkyl moiety thereof is        optionally substituted by hydroxyl group, a morpholinocarbonyl        group, a dialkylaminocarbonyl group, an alkylaminocarbonyl        group, an alkanoylamino group, an alkylthio group, an alkoxy        group, an alkylsulfonyl group, an alkanoyloxy group or a        carboxyl group; dialkylaminoalkylaminocarbonyloxy group; a        piperidinocarbonyloxy group substituted by hydroxyl group, an        alkoxycarbonyl group, a carboxyl group, a        hydroxyalkylaminocarbonyl group, an alkoxyalkylaminocarbonyl        group, an alkylthioalkylaminocarbonyl group, an        alkylsulfinylalkylaminocarbonyl group, an        alkylsulfonylalkylaminocarbonyl group or hydroxyalkyl group;        dialkylaminocarbonyloxy group optionally substituted by hydroxyl        group; a piperidinylaminocarbonyloxy group substituted by a        hydroxyalkanoyl group or an alkoxyalkanoyl group; a        thiomorpholinocarbonyloxy group wherein the sulfur atom is        optionally substituted by an oxo group;        oxopyrrolidinylcarbonyloxy group;        oxotetrahydrothiazolinylcarbonyloxy group;        dialkylaminosulfonylaminocarbonyloxy group; a carboxyl group; an        alkoxycarbonyl group; an aminocarbonyl group optionally        substituted by a pyrimidinyl group or a pyrazinyl group; an        alkylaminocarbonyl group wherein the alkyl moiety is optionally        substituted by hydroxyl group or a cyano group; a        di(hydroxyalkyl)aminocarbonyl group; a pyridylaminocarbonyl        group wherein the pyridyl group moiety is optionally substituted        by hydroxyl group; an aminocarbonyl group substituted by an        alkylpyrido group; a piperidinocarbonyl group substituted by        hydroxyl group or an oxo group; a piperazinocarbonyl group        substituted by an oxo group, an alkyl group, a pyrimidinyl        group, a pyrazinyl group, an alkylsulfonyl group or an alkanoyl        group; a morpholinocarbonyl group; thiomorpholinocarbonyl group;        a pyrrolidinocarbonyl group substituted by a hydroxyalkyl group        or hydroxyl group; an alkylsulfinyl group optionally substituted        by hydroxyl group; a hydroxysulfinyl group; an alkylsulfonyl        group optionally substituted by hydroxyl group or an alkanoyloxy        group; or the group of the formula:    -   wherein R¹¹ is hydrogen atom; a pyridyl group; an alkanoyl group        optionally substituted by a group selected from an alkanoyl        group, an alkylaminocarbonyl group, a dialkylaminocarbonyl        group, an aminocarbonyl group, an amino group, an        alkoxycarbonylamino group, an alkanoylamino group, an amino        group substituted by an alkoxycarbonyl group and an alkyl group,        an amino group substituted by an alkanoyl group and an alkyl        group, a halogen atom, a dialkylamino group, an alkoxy group        optionally substituted by a phenyl group, a furyl group, a        tetrazolyl group, hydroxyl group, an alkylthio group, an        alkylsulfinyl group, an alkylsulfonyl group, 2-aminothiazolyl        group, 2-oxopyrrolidino group, 2,2-dialkyl-1,3-dioxyranyl group,        2-thiol-4-alkylthiazolinyl group, a cycloalkyl group and a        5-alkyl-2,4(1H,3H)pyrimidinedione group; a phenylcarbonyl group        optionally substituted by an amino group or a nitro group; a        pyridylcarbonyl group optionally substituted by an alkyl group        or hydroxyl group; a furylcarbonyl group optionally substituted        by a formyl group, a morpholinoalkyl group or hydroxyalkyl        group; a thienylcarbonyl group; quinolylcarbonyl group; an        indolylcarbonyl group substituted by an alkyl group; a        pyrazinylcarbonyl group optionally substituted by an alkyl group        or an alkanoyl group; a morpholinocarbonyl group; a        pyrrolidinylcarbonyl group optionally substituted by a benzyloxy        group, an alkoxycarbonyl group, an alkanoyl group, hydroxyl        group or an oxo group; tetrahydrofurylcarbonyl group; a        piperidinylcarbonyl group substituted by an alkoxycarbonyl group        or an alkanoyl group; a thiomorpholinocarbonyl group wherein the        sulfur atom is optionally substituted by an oxo group;        3-alkyl-2,4(1H,3H)pyrimidinedionecarbonyl group; an        alkylaminocarbonyl group wherein the alkyl moiety thereof is        optionally substituted by a halogen atom, hydroxyl group or an        alkoxy group; a dialkylaminocarbonyl group; an alkoxycarbonyl        group optionally substituted by an alkoxy group, hydroxyl group        or a halogen atom; an alkylsulfonyl group optionally substituted        by a group selected from hydroxyl group, morpholino group, an        alkylpiperazino group, a dialkylamino group optionally        substituted by hydroxyl group and a halogen atom;        alkenylsulfonyl group; a dialkylamionsulfonyl group; or an alkyl        group optionally substituted by morpholino group, a halogen        atom, an alkoxy group, a cyano group, pyridyl group, a        dialkylaminocarbonyl group or a dialkylamino group, and    -   R¹² is hydrogen atom; pyridyl group; a pyrazinyl group; or an        alkyl group, or    -   —N(R¹¹)(R¹²) is triazolyl group, a tetrazolyl group, an        aminopurinyl group, morpholino group, a morpholinio group        wherein the nitrogen atom is substituted by an alkyl group, an        N-oxomorpholino group, piperidino group optionally substituted        by piperidino group, pyrrolidino group optionally substituted by        hydroxyl group or an alkoxyalkyl group, an imidazolidinyl group        substituted by a hydroxyalkyl group and oxo group, a        hexahydropyrimidinyl group substituted by a hydroxyalkyl group        and oxo group, a dioxopyrrolidino group, a thiazolidyl group or        an azacycloheptyl group,    -   R² is hydrogen atom,    -   Z is an oxygen atom or a group represented by —N(R³)—,    -   R³ is an alkyl group optionally substituted by hydroxyl group or        an alkanoyl group,    -   R⁴ is hydrogen atom or an alkyl group optionally substituted by        hydroxyl group.        Of these, preferred is a compound wherein R¹ is substituted by        hydroxyl group; an alkyl group substituted by a        dialkylaminocarbonyl group, a morpholinocarbonyl group, a        morpholinoaminocarbonyl group or an alkylpiperazinocarbonyl        group; dihydroxyphenylthio group; alkanoylthio group; an        alkylthio group optionally substituted by hydroxyl group; an        alkoxy group optionally substituted by hydroxyl group, an        alkylsulfonyloxy group, a tetrahydropyranyloxy group, a        dialkylamino group, pyridyl group, a triazolyl group, a        tetrazolyl group optionally substituted by an alkyl group,        piperidino group, morpholino group, pyrrolidino group or an        alkoxy group; a morpholinocarbonyloxy group; an        alkylpiperazinocarbonyloxy group; an imidazolylcarbonyloxy        group; a piperidinoalkylaminocarbonyloxy group; a        morpholinoalkylaminocarbonyloxy group; an alkylaminocarbonyloxy        group wherein the alkyl moiety thereof is optionally substituted        by hydroxyl group, a morpholinocarbonyl group or a carboxyl        group; dialkylaminoalkylaminocarbonyloxy group; a piperidino        carbonyloxy group optionally substituted by hydroxyl group or        hydroxyalkyl group; a dialkylaminocarbonyloxy group optionally        substituted by hydroxyl group; a thiomorpholino carbonyloxy        group wherein the sulfur atom is optionally substituted by an        oxo group; an oxopyrrolidinylcarbonyloxy group; an oxo        tetrahydrothiazolinylcarbonyloxy group; a        dialkylaminosulfonylaminocarbonyloxy group; an alkoxycarbonyl        group; an aminocarbonyl group optionally substituted by a        hydroxyalkyl; an alkylsulfinyl group optionally substituted by        hydroxyl group;an alkylsulfonyl group optionally substituted by        hydroxyl group; or a group of the formula:    -   wherein R¹¹ is hydrogen atom ; an alkanoyl group optionally        substituted by a group selected from an amino group, a halogen        atom, a dialkylamino group, an alkoxy group, furyl group, a        tetrazolyl group, hydroxyl group, an alkylthio group, an        alkylsulfinyl group, an alkylsulfonyl group, 2-aminothiazolyl        group, 2,2-dialkyl-1,3-dioxyranyl group,        2-thiol-4-alkylthiazolinyl group, a cycloalkyl group and        5-alkyl-2,4 (1H,3H)pyrimidinedione group; a phenylcarbonyl group        optionally substituted by an amino group or nitro group; a        pyridylcarbonyl group; a furylcarbonyl group optionally        substituted by a formyl group, morpholinoalkyl group or        hydroxyalkyl group; a thienylcarbonyl group; a quinolylcarbonyl        group; a pyrazinylcarbonyl group optionally substituted by an        alkyl group; a morpholinocarbonyl group; pyrrolidinocarbonyl        group; tetrahydrofurylcarbonyl group; a piperidinylcarbonyl        group substituted by an alkoxycarbonyl group; an        alkylaminocarbonyl group optionally substituted by a halogen        atom, hydroxyl group or an alkoxy group; a dialkylaminocarbonyl        group; an alkoxycarbonyl group optionally substituted by an        alkoxy group, hydroxyl group or a halogen atom; an alkylsulfonyl        group optionally substituted by a group selected from hydroxyl        group, morpholino group, an alkylpiperazino group, a        dialkylamino group optionally substituted by hydroxyl group and        a halogen atom; an alkenylsulfonyl group; a dialkylamionsulfonyl        group; or an alkyl group optionally substituted by morpholino        group, a halogen atom, an alkoxy group, cyano group, pyridyl        group, dialkylaminocarbonyl group or a dialkylamino group, and    -   R¹² is hydrogen atom; pyridyl group; or an alkyl group.        Further preferred is a compound wherein R¹ is hydroxyl group; an        alkyl group substituted by a dialkylaminocarbonyl group a        morpholinocarbonyl group, a morpholinoaminocarbonyl group or an        alkylpiperazinocarbonyl group; a dihydroxyphenylthio group; an        alkanoylthio group; an alkylthio group optionally substituted by        hydroxyl group; an alkoxy group optionally substituted by        hydroxyl group, an alkylsulfonyloxy group, a        tetrahydropyranyloxy group, pyridyl group, a triazolyl group, a        tetrazolyl group optionally substituted by an alkyl group or an        alkoxy group; a morpholinocarbonyloxy group; an        imidazolylcarbonyloxy group; a piperidinoalkylaminocarbonyloxy        group; a morpholinoalkylaminocarbonyloxy group; an        alkylaminocarbonyloxy group optionally substituted by hydroxyl        group, a morpholinocarbonyl group or a carboxyl group; a        dialkylaminoalkylaminocarbonyloxy group; a piperidinocarbonyloxy        group optionally substituted by hydroxyl group or hydroxyalkyl        group; a dialkylaminocarbonyloxy group optionally substituted by        hydroxyl group; a thiomorpholinocarbonyloxy group wherein the        sulfur atom is optionally substituted by an oxo group; an        oxopyrrolidinylcarbonyloxy group; an oxotetrahydrothiazolinyl        carbonyloxy group; a dialkylaminosulfonylaminocarbonyloxy group;        an alkoxycarbonyl group; an aminocarbonyl group optionally        substituted by a hydroxyalkyl group; an alkylsulfinyl group        optionally substituted by hydroxyl group; an alkylsulfonyl group        optionally substituted by hydroxyl group; or, a group of the        formula:    -   wherein R¹¹ is an alkanoyl group optionally substituted by a        group selected from an amino group, a halogen atom, an alkoxy        group, a furyl group, a tetrazolyl group, hydroxyl group, an        alkylthio group, an alkylsulfinyl group, an alkylsulfonyl group,        2-aminothiazolyl group, 2,2-dialkyl-1,3-dioxyranyl group,        2-thiol-4-alkylthiazolinyl group, a cycloalkyl group and        5-alkyl-2,4(1H,3H)pyrimidinedione group; a phenylcarbonyl group        optionally substituted by an amino group or a nitro group; a        pyridylcarbonyl group; a furylcarbonyl group optionally        substituted by a formyl group or a hydroxyalkyl group; a        quinolylcarbonyl group; a morpholinocarbonyl group; a        pyrrolidinocarbonyl group; a tetrahydrofurylcarbonyl group; a        piperidinylcarbonyl group substituted by an alkoxycarbonyl        group; an alkylaminocarbonyl group optionally substituted by a        halogen atom, hydroxyl group or an alkoxy group; a        dialkylaminocarbonyl group; an alkoxycarbonyl group optionally        substituted by an alkoxy group, hydroxyl group or a halogen        atom; an alkylsulfonyl group optionally substituted by hydroxyl        group or a halogen atom; an alkenylsulfonyl group; or a        thienylsulfonyl group, and    -   R¹² is hydrogen atom; pyridyl group; or an alkyl group.

In the compound of the present invention, as a preferred compound thereis mentioned a compound wherein Ring A is a benzene ring of the formula:

and Ring B is a benzene ring of the formula:

-   -   wherein A¹ is an alkyl group, hydrogen atom, a halogen atom or        an alkoxy group, A² is hydrogen atom or a halogen atom, A³ is        hydrogen atom , B¹ is a trihalogenoalkyl group, hydrogen atom or        an alkyl group, B² is a trihalogenoalkyl group, hydrogen atom or        an alkyl group, B³ is hydrogen atom,    -   R¹ is hydroxyl group; an alkyl group substituted by a        dialkylaminocarbonyl group, a morpholinocarbonyl group, hydroxyl        group, an alkoxycarbonyl group or a hydroxyalkylaminocarbonyloxy        group; dihydroxyphenylthionyl group; alkanoylthio group; an        alkylthio group optionally substituted by hydroxyl group, an        alkylaminocarbonyl group, a dialkylaminocarbonyl group, an        alkoxycarbonylamino group, hydroxyalkanoylamino group, a        morpholinocarbonylamino group, a hydroxyalkylaminocarbonylamino        group or an alkanoyloxy group; dialkylthionium group; an alkoxy        group optionally substituted by hydroxyl group, an        alkylsulfonyloxy group, a tetrahydropyranyloxy group, a        triazolyl group, a tetrazolyl group optionally substituted by an        alkyl group, or an alkoxy group; thienylsulfonyloxy group;        morpholinocarbonyloxy group; imidazolylcarbonyloxy group; an        alkylaminocarbonyloxy group wherein the alkyl moiety thereof is        optionally substituted by hydroxyl group, a morpholinocarbonyl        group, a dialkylaminocarbonyl group, an alkylaminocarbonyl        group, an alkanoylamino group, an alkylthio group, an alkoxy        group, an alkylsulfonyl group, an alkanoyloxy group or a        carboxyl group; a piperidinocarbonyloxy group substituted by        hydroxyl group, an alkoxycarbonyl group, a carboxyl group, a        hydroxyalkylaminocarbonyl group, an alkoxyalkylaminocarbonyl        group, an alkylthioalkylaminocarbonyl group, an        alkylsulfinylalkylaminocarbonyl group, an        alkylsulfonylalkylaminocarbonyl group or hydroxyalkyl group;        dialkylaminocarbonyloxy group optionally substituted by hydroxyl        group; a piperidinylaminocarbonyloxy group substituted by a        hydroxyalkanoyl group or an alkoxyalkanoyl group; a        thiomorpholinocarbonyloxy group wherein the sulfur atom is        optionally substituted by an oxo group;        oxopyrrolidinylcarbonyloxy group;        oxotetrahydrothiazolinylcarbonyloxy group;        dialkylaminosulfonylaminocarbonyloxy group; a carboxyl group; an        alkoxycarbonyl group; an aminocarbonyl group optionally        substituted by a pyrimidinyl group; an alkylaminocarbonyl group        wherein the alkyl moiety is optionally substituted by hydroxyl        group or a cyano group; a di(hydroxyalkyl)aminocarbonyl group; a        pyridylaminocarbonyl group wherein the pyridyl group moiety is        optionally substituted by hydroxyl group; an aminocarbonyl group        substituted by an alkylpyrido group; a piperidinocarbonyl group        substituted by hydroxyl group or an oxo group; a        piperazinocarbonyl group substituted by an oxo group, an alkyl        group, an alkylsulfonyl group or an alkanoyl group; a        morpholinocarbonyl group; thiomorpholinocarbonyl group; a        pyrrolidinocarbonyl group substituted by a hydroxyalkyl group or        hydroxyl group; an alkylsulfinyl group optionally substituted by        hydroxyl group; a hydroxysulfinyl group; an alkylsulfonyl group        optionally substituted by hydroxyl group or an alkanoyloxy        group; or the group of the formula:    -   wherein R¹¹ is an alkanoyl group optionally substituted by (a)        group(s) selected from an alkanoyl group, an alkylaminocarbonyl        group, a dialkylaminocarbonyl group, an aminocarbonyl group, an        alkoxycarbonylamino group, an alkanoylamino group, an amino        group substituted by an alkoxycarbonyl group and an alkyl group,        an amino group substituted by an alkanoyl group and an alkyl        group, an alkoxy group optionally substituted by a phenyl group,        a furyl group, a tetrazolyl group, hydroxyl group, an alkylthio        group, an alkylsulfinyl group, an alkylsulfonyl group,        2-aminothiazolyl group, 2-oxopyrrolidino group,        2,2-dialkyl-1,3-dioxyranyl group, 2-thiol-4-alkylthiazolinyl        group and a cycloalkyl group; a phenylcarbonyl group optionally        substituted by an amino group or a nitro group; a        pyridylcarbonyl group optionally substituted by hydroxyl group;        a furylcarbonyl group optionally substituted by a formyl group,        or hydroxyalkyl group; a thienylcarbonyl group; an        indolylcarbonyl group substituted by an alkyl group; a        morpholinocarbonyl group; a pyrrolidinylcarbonyl group        optionally substituted by a benzyloxy group, an alkoxycarbonyl        group, an alkanoyl group, hydroxyl group or an oxo group;        tetrahydrofurylcarbonyl group; a piperidinylcarbonyl group        substituted by an alkoxycarbonyl group or an alkanoyl group; a        thiomorpholinocarbonyl group wherein the sulfur atom is        optionally substituted by an oxo group;        3-alkyl-2,4(1H,3H)pyrimidinedionecarbonyl group; an        alkylaminocarbonyl group wherein the alkyl moiety thereof is        optionally substituted by a halogen atom, hydroxyl group or an        alkoxy group; a dialkylaminocarbonyl group; an alkoxycarbonyl        group optionally substituted by an alkoxy group, hydroxyl group        or a halogen atom; an alkylsulfonyl group optionally substituted        by a group selected from hydroxyl group, and a halogen atom;        alkenylsulfonyl group; or a dialkylamionsulfonyl group; and    -   R¹² is hydrogen atom; a pyrazinyl group; or an alkyl group, or    -   —N(R¹¹)(R¹²) is triazolyl group, a tetrazolyl group, an        aminopurinyl group, a morpholinio group wherein the nitrogen        atom is substituted by an alkyl group, an N-oxomorpholino group,        an imidazolidinyl group substituted by a hydroxyalkyl group and        oxo group, a hexahydropyrimidinyl group substituted by a        hydroxyalkyl group and oxo group, or a dioxopyrrolidino group,    -   R² is hydrogen atom,    -   Z is an oxygen atom or a group represented by —N(R³)—,    -   R³ is an alkyl group optionally substituted by hydroxyl group,    -   R⁴ is hydrogen atom or an alkyl group optionally substituted by        hydroxyl group.

Of these, preferred is a compound wherein Ring A is a benzene ring ofthe formula:

and Ring B is a benzene ring of the formula:

-   -   wherein A¹ is an alkyl group, A² is a halogen atom, A³ is        hydrogen atom, B¹ is a trihalogenoalkyl group, B² is a        trihalogenoalkyl group, B³ is hydrogen atom,    -   R¹ is an alkoxy group substituted by hydroxyl group or        tetrahydropyranyloxy; an alkylaminocarbonyloxy group wherein the        alkyl moiety thereof is optionally substituted by hydroxyl        group; a thiomorpholinocarbonyloxy group wherein the sulfur atom        is substituted by an oxo group; an alkylthionyl group; an        alkanoyl group substituted by hydroxyl group; aminocarbonyl        group substituted by (a) group(s) selected from an alkyl group,        pyrazinyl group and pyrimidinyl group; piperzinocarbonyl group        substituted by an alkanoyl group; piperidinocarbonyl group        substituted by hydroxyl group; an alkylsulfinyl group optionally        substituted by hydroxyl group; an alkylsulfonyl group optionally        substituted by hydroxyl group; or the group the formula:    -   wherein R¹¹ is an alkanoyl group optionally substituted by (a)        group(s) selected from an alkoxy group, hydroxyl group and a        cycloalkyl group; an alkoxycarbonyl group; a pyridylcarbonyl        group substituted by hydroxyl group; a morpholinocarbonyl group;        an alkylaminocarbonyl group; or an alkylsulfonyl group;        pyrazinyl group, and    -   R¹² is hydrogen atom, or an alkyl group,    -   —N(R¹¹)(R¹²) is triazolyl group, tetrazolyl group or an        N-oxomorpholino group,    -   R² is hydrogen atom,    -   Z is a group represented by —N(R³)—,    -   R³ is an alkyl group,    -   R⁴ is hydrogen atom or an alkyl group.

Further more preferred is a compound wherein R¹ is analkylaminocarbonyloxy group wherein the alkyl moiety thereof issubstituted by hydroxyl group; a thiomorpholinocarbonyloxy group whereinthe sulfur atom is substituted by an oxo group; an alkanoyl groupsubstituted by hydroxyl group; piperzinocarbonyl group substituted by analkanoyl group; piperidinocarbonyl group substituted by hydroxyl group;an alkylsulfinyl group substituted by hydroxyl group; an alkylsulfonylgroup optionally substituted by hydroxyl group; or the group theformula:

-   -   wherein R¹¹ is an alkanoyl group substituted by hydroxylgroup,        and    -   R¹² is hydrogen atom.

In the present invention, particularly preferred compound is a compoundselected from the following (A) to (BK) or pharmaceutically acceptablesalt thereof.

-   -   (A)        (2R,4S)-1-[N-{1-(S)-(3,5-bistrifluoromethylphenyl)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-(2-methylpropionylamino)piperidine,    -   (B)        (2R,4S)-1-{N-(3,5-bistrifluoromethylbenzyl)-N-methyl}-aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-morpholino-carbonylaminopiperidine,    -   (C)        (2R,4S)-1-(N-(3,5-bistrifluoromethylbenzyl)-N-methyl}-aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-(2-hydroxyethoxy)-piperidine,    -   (D)        (2R,4S)-1-[N-(1-(R)-(3,5-bistrifluoromethylphenyl)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-{2-(2-tetrahydropyranyloxy)ethoxy}piperidine,    -   (E)        (2R,4S)-1-[N-{1-(S)-(3,5-bistrifluoromethylphenyl)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-methoxy-acetylaminopiperidine,    -   (F)        (2R,4S)-1-[N-{1-(S)-(3,5-bistrifluoromethylphenyl)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-methoxy-carbonylaminopiperidine,    -   (G)        (2R,4S)-1-[N-{1-(S)-(3,5-bistrifluoromethylphenyl)ethyl}-N-methyl]aminocarbonyl-4-ethoxycarbonylamino-2-(4-fluoro-2-methylphenyl)piperidine,    -   (H)        (2R,4S)-1-[N-{1-(S)-(3,5-bistrifluoromethylphenyl)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-metansurfonylaminopiperidine,    -   (I)        (2R,4S)-1-[N-{1-(S)-(3,5-bistrifluoromethylphenyl)ethyl)-N-methyl]aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-(2-hydroxyethoxy)piperidine,    -   (J)        (2R,4S)-1-[N-{1-(R)-(3,5-bistrifluoromethylphenyl)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-hydroxy-acetylaminopiperidine,    -   (K)        (2R,4S)-1-[N-{1-(R)-(3,5-bistrifluoromethylphenyl)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-(3-hydroxypropoxy)piperidine,    -   (L)        (2R,4S)-1-[N-{1-(S)-(3,5-bistrifluoromethylphenyl)ethyl}-N-methyl]aminocarbonyl-4-(2-cyclopropyl-2-hydroxyacetylamino)-2-(4-fluoro-2-methylphenyl)piperidine,    -   (M)        (2R,4S)-1-[N-{1-(S)-(3,5-bistrifluoromethylphenyl)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-(2-hydroxy-2-methylpropionylamino)piperidine,    -   (N)        (2R,4S)-1-[N-{1-(S)-(3,5-bistrifluoromethylphenyl)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-((S)-3-hydroxybutyrylamino)piperidine,    -   (O)        (2R,4S)-1-{N-(3,5-bistrifluoromethylbenzyl)-N-methyl}-aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-(2-hydroxyethyl-aminocarbonyloxy)piperidine,    -   (P)        (2R,4S)-1-(N-{1-(R)-(3,5-bistrifluoromethylphenyl)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-methanesulfinylpiperidine,    -   (Q)        (2R,4S)-1-(N-{1-(R)-(3,5-bistrifluoromethylphenyl)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-methanesulfonylpiperidine,    -   (R)        (2R,4S)-1-{N-(3,5-bistrifluoromethylbenzyl)-N-methyl}-aminocarbonyl-4-ethylaminocarbonyloxy-2-(4-fluoro-2-methyl-phenyl)piperidine,    -   (S)        (2R,4S)-1-[N-{1-(S)-(3,5-bistrifluoromethylphenyl)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-(2-methoxypropionylamino)piperidine,    -   (T)        (2R,4S)-1-[N-{1-(R)-(3,5-bistrifluoromethylphenyl)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-(N-methanesulfonyl-N-methylamino)piperidine,    -   (U)        (2R,4S)-1-[N-{1-(R)-(3,5-bistrifluoromethylphenyl)ethyl)-N-methyl]aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-(2-hydroxyethylaminocarbonyloxy)piperidine,    -   (V)        (2R,4S)-1-[N-{1-(S)-(3,5-bistrifluoromethylphenyl)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-(3-hydroxy-3-methylbutyrylamino)piperidine,    -   (W)        (2R,4S)-1-{N-(3,5-bistrifluoromethylbenzyl)-N-methyl}-aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-(2-hydroxyethane-sulfinyl)piperidine,    -   (X)        (2R,4S)-1-[N-{1-(S)-(3,5-bistrifluoromethylphenyl)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-hydroxy-acetylaminopiperidine,    -   (Y)        (2R,4S)-1-[N-{1-(S)-(3,5-bistrifluoromethylphenyl)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-((S)-2-hydroxypropionylamino)piperidine,    -   (Z)        (2R,4S)-1-[N-{1-(S)-(3,5-bistrifluoromethylphenyl)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-((R)-3-hydroxybutyrylamino)piperidine,    -   (AA)        (2R,4S)-1-(N-(3,5-bistrifluoromethylbenzyl)-N-methyl}-aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-(2-hydroxy-2-methylpropanesulfonyl)piperidine,    -   (AB)        (2R,4S)-1-[N-{1-(R)-(3,5-bistrifluoromethylphenyl)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-(2-hydroxyethanesulfinyl)piperidine,    -   (AC)        (2R,4S)-1-[N-{1-(R)-(3,5-bistrifluoromethylphenyl)ethyl)-N-methyl]aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-{(S)—((S)-2-hydroxypropane)sulfinyl}piperidine,    -   (AD)        (2R,4S)-1-[N-{1-(R)-(3,5-bistrifluoromethylphenyl)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-{(R)—((S)-2-hydroxypropane)sulfinyl}piperidine,    -   (AE)        (2R,4S)-1-(N-(3,5-bistrifluoromethylbenzyl)-N-methyl}-aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-(2-hydroxy-2-methylpropanesulfinyl)piperidine,    -   (AF)        (2R,4S)-1-[N-{1-(R)-(3,5-bistrifluoromethylphenyl)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-((S)-2-hydroxypropanesulfonyl)piperidine,    -   (AG)        (2R,4S)-1-[N-{1-(R)-(3,5-bistrifluoromethylphenyl)ethyl)-N-methyl]aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-(1-methylethanesulfonyl)piperidine,    -   (AH)        (2R,4S)-1-[N-{1-(R)-(3,5-bistrifluoromethylphenyl)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-(2-hydroxy-2-methylpropanesulfinyl)piperidine,    -   (AI)        (2R,4S)-1-{N-(3,5-bistrifluoromethylbenzyl)-N-methyl}-aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-{(S)—((S)-2-hydroxypropane)sulfinyl}piperidine,    -   (AJ)        (2R,4S)-1-{N-(3,5-bistrifluoromethylbenzyl)-N-methyl}-aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-{(R)—((S)-2-hydroxypropane)sulfinyl}piperidine,    -   (AK)        (2R,4S)-1-(N-(3,5-bistrifluoromethylbenzyl)-N-methyl}-aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-{(R)—((R)-2-hydroxypropane)sulfinyl}piperidine,    -   (AL)        (2R,4S)-1-(N-(3,5-bistrifluoromethylbenzyl)-N-methyl)-aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-{(S)—((R)-2-hydroxypropane)sulfinylipiperidine,    -   (AM)        (2R,4S)-1-{N-(3,5-bistrifluoromethylbenzyl)-N-methyl}-aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-((S)-2-hydroxy-propanesulfonyl)piperidine,    -   (AN)        (2R,4S)-1-{N-(3,5-bistrifluoromethylbenzyl)-N-methyl}-aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-((S)-3-hydroxy-butyrylamino)piperidine,    -   (AO)        (2R,4S)-1-{N-(3,5-bistrifluoromethylbenzyl)-N-methyl}-aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-((R)-3-hydroxy-butyrylamino)piperidine,    -   (AP)        (2R,4S)-4-(4-acetylpiperazinocarbonyl)-1-[N-{1-(R)-(3,5-bistrifluoromethylphenyl)ethyl)-N-methyl]aminocarbonyl-2-(4-fluoro-2-methylphenyl)piperidine,    -   (AQ)        (2R,4S)-1-{N-(3,5-bistrifluoromethylbenzyl)-N-methyl}-aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-(1-methyl-ethanesulfinyl)piperidine,    -   (AR)        (2R,4S)-1-{N-(3,5-bistrifluoromethylbenzyl)-N-methyl}-aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-(1-oxothio-morpholinocarbonyloxy)piperidine,    -   (AS)        (2R,4S)-1-{N-(3,5-bistrifluoromethylbenzyl)-N-methyl}-aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-(2-hydroxy-ethanesulfonyl)piperidine,    -   (AT)        (2R,4S)-1-{N-(3,5-bistrifluoromethylbenzyl)-N-methyl}-aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-(1-methyl-ethanesulfonyl)piperidine,    -   (AU)        (2R,4S)-1-[N-{1-(R)-(3,5-bistrifluoromethylphenyl)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-(4-hydroxypiperidinocarbonyl)piperidine,    -   (AV)        (2R,4S)-1-{N-(3,5-bistrifluoromethylbenzyl)-N-methyl}-aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-methanesulfonyl-piperidine,    -   (AW)        (2R,4S)-1-{N-(3,5-bistrifluoromethylbenzyl)-N-methyl}-aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-((R)-2-hydroxy-propionyl)piperidine,    -   (AX)        (2R,4S)-1-{N-(3,5-bistrifluoromethylbenzyl)-N-methyl}-aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-(N-methyl-N-pyrazin-2-ylaminocarbonyl)piperidine,    -   (AY)        (2R,4S)-1-{N-(3,5-bistrifluoromethylbenzyl)-N-methyl}-aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-(pyrazin-2-yl-amino)piperidine,    -   (AZ)        (2R,4S)-1-{N-(3,5-bistrifluoromethylbenzyl)-N-methyl}-aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-(N-methyl-N-pyrazin-2-ylamino)piperidine,    -   (BA)        (2R,4S)-1-[N-{1-(R)-(3,5-bistrifluoromethylphenyl)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-(1-methylethylthionyl)piperidine,    -   (BB)        (2R,4S)-1-[N-{1-(R)-(3,5-bistrifluoromethylphenyl)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-(1-triazoryl)piperidine,    -   (BC)        (2R,4S)-1-[N-(1-(R)-(3,5-bistrifluoromethylphenyl)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-(1-tetrazoryl)piperidine,    -   (BD)        (2R,4S)-1-[N-{1-(S)-(3,5-bistrifluoromethylphenyl)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-(N-oxo-morphorino)piperidine,    -   (BE)        (2R,4S)-1-[N-{1-(R)-(3,5-bistrifluoromethylphenyl)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-(N-oxo-morphorino)piperidine,    -   (BF)        (2R,4S)-1-{N-(3,5-bistrifluoromethylbenzyl)-N-methyl}-aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-(N-oxomorphorino)-piperidine,    -   (BG)        (2R,4S)-1-{N-(3,5-bistrifluoromethylbenzyl)-N-methyl}-aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-(2-hydroxypyridin-5-yl-carbonylamino)piperidine,    -   (BH)        (2R,4S)-1-[N-{1-(R)-(3,5-bistrifluoromethylphenyl)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-(N-pyrimidin-4-ylaminocarbonyl)piperidine,    -   (BI)        (2R,4S)-1-[N-{1-(R)-(3,5-bistrifluoromethylphenyl)ethyl)-N-methyl]aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-(N-methyl-N-pyrimidin-4-ylaminocarbonyl)piperidine,    -   (BJ)        (2R,4S)-1-[N-(1-(S)-(3,5-bistrifluoromethylphenyl)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-(2-hydroxyacetylamino)piperidine,        or    -   (BK)        (2R,4S)-1-[N-{1-(R)-(3,5-bistrifluoromethylphenyl)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-(1-methylethylthio)piperidine.

In the present invention, more particularly preferred compound is acompound selected from the following (a) to (s) or a pharmaceuticallyacceptable salt thereof.

-   -   (a)        (2R,4S)-1-[N-{1-(S)-(3,5-bistrifluoromethylphenyl)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-(2-hydroxy-2-methylpropionylamino)piperidine,    -   (b)        (2R,4S)-1-[N-{1-(S)-(3,5-bistrifluoromethylphenyl)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-((S)-3-hydroxybutyrylamino)piperidine,    -   (c)        (2R,4S)-1-{N-(3,5-bistrifluoromethylbenzyl)-N-methyl}-aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-(2-hydroxyethyl-aminocarbonyloxy)piperidine,    -   (d)        (2R,4S)-1-[N-{1-(S)-(3,5-bistrifluoromethylphenyl)ethyl}-N-methyl)aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-(3-hydroxy-3-methylbutyrylamino)piperidine,    -   (e)        (2R,4S)-1-[N-{1-(S)-(3,5-bistrifluoromethylphenyl)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-((R)-3-hydroxybutyrylamino)piperidine,    -   (f)        (2R,4S)-1-{N-(3,5-bistrifluoromethylbenzyl)-N-methyl}-aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-(2-hydroxy-2-methylpropanesulfonyl)piperidine,    -   (g)        (2R,4S)-1-{N-(3,5-bistrifluoromethylbenzyl)-N-methyl}-aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-(2-hydroxy-2-methylpropanesulfinyl)piperidine,    -   (h)        (2R,4S)-1-{N-(3,5-bistrifluoromethylbenzyl)-N-methyl}-aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-((S)-2-hydroxy-propanesulfonyl)piperidine,    -   (i)        (2R,4S)-1-{N-(3,5-bistrifluoromethylbenzyl)-N-methyl}-aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-((S)-3-hydroxy-butyrylamino)piperidine,    -   (j)        (2R,4S)-1-{N-(3,5-bistrifluoromethylbenzyl)-N-methyl}-aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-((R)-3-hydroxy-butyrylamino)piperidine,    -   (k)        (2R,4S)-4-(4-acetylpiperazinocarbonyl)-1-[N-{1-(R)-(3,5-bistrifluoromethylphenyl)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-methylphenyl)piperidine,    -   (l)        (2R,4S)-1-{N-(3,5-bistrifluoromethylbenzyl)-N-methyl)-aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-(1-oxothio-morpholinocarbonyloxy)piperidine,    -   (m)        (2R,4S)-1-{N-(3,5-bistrifluoromethylbenzyl)-N-methyl}-aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-(2-hydroxy-ethanesulfonyl)piperidine,    -   (n)        (2R,4S)-1-{N-(3,5-bistrifluoromethylbenzyl)-N-methyl}-amino-carbonyl-2-(4-fluoro-2-methylphenyl)-4-(1-methyl-ethanesulfonyl)piperidine,    -   (o)        (2R,4S)-1-[N-{1-(R)-(3,5-bistrifluoromethylphenyl)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-(4-hydroxypiperidinocarbonyl)piperidine,    -   (p)        (2R,4S)-1-{N-(3,5-bistrifluoromethylbenzyl)-N-methyl}-aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-methanesulfonyl-piperidine,    -   (q)        (2R,4S)-1-{N-(3,5-bistrifluoromethylbenzyl)-N-methyl}-aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-((R)-2-hydroxy-propionyl)piperidine,    -   (r)        (2R,4S)-1-(N-{1-(S)-(3,5-bistrifluoromethylphenyl)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-(2-hydroxyacetylamino)piperidine,        or    -   (s)        (2R,4S)-1-[N-{1-(R)-(3,5-bistrifluoromethylphenyl)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-(1-methylethylthio)piperidine.

In the compound of the present invention, as a preferred compound thereis mentioned a compound wherein Ring A is a benzene ring of the formula:

and Ring B is a benzene ring of the formula:

-   -   wherein A¹ is an alkyl group, A² is a halogen atom, A³ is        hydrogen atom , B¹ is a trihalogenoalkyl group or a halogen        atom, B² is a trihalogenoalkyl group or a halogen atom, B³ is        hydrogen atom,    -   R¹ is hydroxyl group; an alkyl group substituted by a        dialkylaminocarbonyl group or a morpholinocarbonyl group, an        alkoxy group optionally substituted by hydroxyl group, an        alkylsulfonyloxy group, a triazolyl group, or a tetrazolyl group        optionally substituted by an alkyl group; morpholino-carbonyloxy        group; a hydroxyalkylaminocarbonyloxy group; an        imidazolylcarbonyloxy group; an alkylsulfinyl group optionally        substituted by hydroxyl group; an alkylsulfonyl group; an        alkylaminocarbonyl group substituted by hydroxyl group; a        piperidinocarbonyl group substituted by hydroxyl group; or a        group of the formula:    -   wherein R¹¹ is an alkanoyl group optionally substituted by        hydroxyl group or a 5-alkyl-2,4(1H,3H)pyrimidine-dione group; a        pyridylcarbonyl group; a furylcarbonyl group; a thienylcarbonyl        group; a morpholinocarbonyl group; an alkoxycarbonyl group; or        an alkylsulfonyl group;    -   R¹² is hydrogen atom; or an alkyl group, or    -   —N(R¹¹)(R¹²) is triazolyl group, a morpholinio group wherein the        nitrogen atom is substituted by an alkyl group, or an        N-oxomorpholino group,    -   R² is hydrogen atom,    -   Z is a group represented by —N(R³)—,    -   R³ is an alkyl group,    -   R⁴ is hydrogen atom or an alkyl group.        Of these, preferred is a compound wherein R¹ is hydroxyl group;        an alkyl group substituted by a dialkylaminocarbonyl group or a        morpholinocarbonyl group; an alkoxy group optionally substituted        by hydroxyl group, alkylsulfonyloxy group, a triazolyl group, or        a tetrazolyl group optionally substituted by an alkyl group; a        morpholinocarbonyloxy group; a hydroxyalkylaminocarbonyloxy        group; an imidazolylcarbonyloxy group; an alkylsulfinyl group        optionally substituted by hydroxyl group; an alkylsulfonyl        group; an alkylaminocarbonyl group substituted by hydroxyl        group; a piperidinocarbonyl group substituted by hydroxyl group;        or a group of the formula:    -   wherein R¹¹ is an alkanoyl group optionally substituted by        hydroxyl group or 5-alkyl-2,4(1H,3H)pyrimidinedione group; a        pyridylcarbonyl group; a furylcarbonyl group; a thienylcarbonyl        group; a morpholinocarbonyl group; an alkoxycarbonyl group; an        alkylsulfonyl group;    -   R¹² is hydrogen atom; or an alkyl group.

In the compounds of the present invention, more preferred is a compoundwherein R¹ is hydroxyl group; an alkoxy group substituted by. hydroxylgroup, or a triazolyl group; a hydroxyalkylaminocarbonyloxy group; analkylsulfinyl group optionally substituted by hydroxyl group; analkylsulfonyl group; an alkylaminocarbonyl group substituted by hydroxylgroup; a piperidinocarbonyl group substituted by hydroxyl group; or agroup of the formula:

-   -   wherein R¹¹ is an alkanoyl group optionally substituted by        hydroxyl group; and    -   R¹² is hydrogen atom; or an alkyl group, or    -   —N(R¹¹)(R¹²) is a morpholinio group wherein the nitrogen atom is        substituted by an alkyl group, a piperazino group substituted by        an N-oxomorpholino group, an alkyl group or an alkanoyl group,    -   R² is hydrogen atom,    -   Z is a group represented by —N(R³)—,    -   R³ is an alkyl group,    -   R⁴ is hydrogen atom or an alkyl group.

The more preferred is the compound wherein R¹ is hydroxyl group; analkoxy group substituted by hydroxyl group, or a triazolyl group; ahydroxyalkylaminocarbonyloxy group; an alkylsulfinyl group optionallysubstituted by hydroxyl group; an alkylsulfonyl group; analkylaminocarbonyl group substituted by hydroxyl group; apiperidinocarbonyl group substituted by hydroxyl group; or a group ofthe formula:

-   -   wherein R¹¹ is an alkanoyl group optionally substituted by        hydroxyl group;    -   R¹² is hydrogen atom; or an alkyl group.

In the compound of the present invention, other preferred compound is acompound wherein R¹ is hydroxyl group; an alkoxy group optionallysubstituted by hydroxyl group, an alkylsulfonyloxy group or a tetrazolylgroup; a hydroxyalkylaminocarbonyloxy group; an alkylsulfinyl groupoptionally substituted by hydroxyl group; an alkylsulfonyl group; analkylaminocarbonyl group substituted by hydroxyl group; apiperidinocarbonyl group substituted by hydroxyl group; or a group ofthe formula:

-   -   wherein R¹¹ is an alkanoyl group optionally substituted by        hydroxyl group; a furylcarbonyl group; a morpholinocarbonyl        group; an alkoxycarbonyl group; or an alkylsulfonyl group; and    -   R¹² is hydrogen atom; or an alkyl group, or    -   —N(R¹¹)(R¹²) is a triazolyl group, or a tetrazolyl group,    -   R² is hydrogen atom,    -   Z is a group represented by —N(R³)—,    -   R³ is an alkyl group,    -   R⁴ is hydrogen atom or an alkyl group.

Another preferred compound is exemplified by the compound wherein Ring Ais a benzene ring of the formula:

and Ring B is a benzene ring of the formula:

-   -   wherein A¹ is an alkyl group, A² is a halogen atom, A³ is        hydrogen atom, B¹ is a trihalogenoalkyl group, B² is a        trihalogenoalkyl group, B³ is hydrogen atom,    -   R¹ is a hydroxyalkylaminocarbonyloxy group; an alkylsulfinyl        group optionally substituted by hydroxyl group; an alkylsulfonyl        group; an alkylaminocarbonyl group substituted by hydroxyl        group; a piperidinocarbonyl group substituted by hydroxyl group;        or a group of the formula:    -   wherein R¹¹ is an alkanoyl group optionally substituted by        hydroxyl group; or an alkoxycarbonyl group; and    -   R¹² is hydrogen atom;or an alkyl group    -   R² is hydrogen atom,    -   Z is a group represented by —N(R³)—,    -   R³ is an alkyl group,    -   R⁴ is hydrogen atom or an alkyl group.

Still another preferred compound is a compound wherein Ring A is abenzene ring of the formula:

and Ring B is a benzene ring of the formula:

-   -   wherein A¹ is an alkyl group, A² is a halogen atom, A³ is        hydrogen atom , B¹ is a trihalogenoalkyl group, B² is a        trihalogenoalkyl group, B³ is hydrogen atom,    -   R¹ is a hydroxyalkylaminocarbonyloxy group; an alkylsulfinyl        group optionally substituted by hydroxyl group; an alkylsulfonyl        group; an alkylaminocarbonyl group substituted by hydroxyl        group; a piperidinocarbonyl group substituted by hydroxyl group;        or a group of the formula:    -   wherein R¹¹ is an alkanoyl group optionally substituted by        hydroxyl group, and    -   R¹² is hydrogen atom; or an alkyl group, or    -   —N(R¹¹)(R¹²) is a morpholinio group wherein the nitrogen atom is        substituted by an alkyl group, or an N-oxomorpholino group,    -   R² is hydrogen atom,    -   Z is a group represented by —N(R³)—,    -   R³ is an alkyl group,    -   R⁴ is hydrogen atom or an alkyl group.

More preferred is a compound wherein R¹ is ahydroxyalkylaminocarbonyloxy group; an alkylsulfinyl group optionallysubstituted by hydroxyl group; an alkylsulfonyl group; analkylaminocarbonyl group substituted by hydroxyl group; apiperidinocarbonyl group substituted by hydroxyl group; or a group ofthe formula:

-   -   wherein R¹¹ is an alkanoyl group optionally substituted by        hydroxyl group, and R¹² is hydrogen atom; or an alkyl group.

The compound [I] of the present invention can be used for apharmaceuticl use either in a free form or in form of a pharmaceuticallyacceptable salt.

As the pharmaceutically acceptable salt of the compound [I] of thepresent invention, there may be mentioned, for example, an inorganicacid salt such as hydrochloride, sulfate, phosphate and hydrobromate;and an organic acid salt etc., such as acetate, fumarate, oxalate,citrate, methanesulfonate, benzenesulfonate, tosylate, maleate,succinate and tartarate.

Further, the compound [I] of the present invention or a pharmaceuticallyacceptable salt thereof includes any of its internal salts, solvate andhydrates, etc.

Although an optical isomer based on an asymmetric carbon can be presentin the compound [I] of the present invention, the present inventionincludes any of these optical isomers and the mixture thereof. In thepresent invention, among these optical isomers, preferred is a compoundhaving R configuration at 2-position of the piperidine ring (theconnecting position of Ring A), and particularly preferred is a compoundhaving R configuration at the second position of the piperidine ring(the connecting position of Ring A) and S configuration at 4-position(the connecting position of R¹).

The compound [I] or a pharmaceutically acceptable salt thereof of thepresent invention has an excellent tachykinin receptor antagonisticaction, particularly an SP receptor antagonistic action, whereby it isuseful as a safe medicament for prophylaxis and treatment forinflammation or allergic diseases (for example, atopic dermatitis,dermatitis, herpes, proriasis, asthma, bronchitis, expectoration,rhinitis, rheumatoid arthritis, osteoarthritis, osteoporosis, multiplesclerosis, conjunctivitis, ophthalmia, cystitis, etc.), pain, migraine,neuralgia, itchiness, cough, and further central nervous system diseases(for example, schizophrenia, Parkinson's disease, depression,uneasiness, psychosomatic disorder, morphine dependence, dementia (forexample, Alzheimer's disease, etc.), etc.), digestive organs disease(for example, hypersensitive bowel disease, ulcerative colitis, Crohn'sdisease, disorder (for example, gastritis, gastric ulcer, etc.) relatedto urease-positive Spirillum (for example, helicobacter pylori, etc.),etc.), nausea, emesis, urinary disorder (for example, pollakiurea,urinary incontinence, etc.), circulatory disease (for example, anginapectoris, hypertension, cardiac failure, thrombosis, etc.) and immunedisorder, etc. in mammals (for example, mouse, Mongolian gerbil, ferret,rat, hamster, rabbit, cat, dog, bovine, sheep, monkey, human, etc.).Particularly, since compound [I] or a pharmaceutically acceptable saltthereof which is an active ingredient of the present invention is highlytransportable in the brain and at the same time has a low toxicity,showing almost no side effect, it is useful as a therapeutic orprophylactic agent for central nerve system disease such as emesis,depression and so forth, or urinary disorder such as pollakiuria, etc.

Measurements on the compound of the present invention or apharmaceutically acceptable salt thereof can be carried out, accordingto the method described in European Journal of Pharmacology, vol. 254,pages 221-227 (1994) with respect to a neurokinin-1 receptor bindingaction, and according to the method described in European Journal ofPharmacology) vol. 265, pages 179-183 (1994) with respect to an actionagainst the neurokinin-1 receptor induction, and according to the methoddescribed in British Journal of Pharmacology vol. 119, pages 931-936(1996) with regard to the effect against emesis, further according tothe method described in Journal of Urology, vol. 155, No. 1, pages355-360 (1996) with regard to an inhibitory action on pollakiuria.

The compound [I] or a pharmaceutically acceptable salt thereof of thepresent invention can be administered orally or parenterally, and it canbe formulated into a suitable preparation, using a conventionally usedpharmaceutical carrier for an oral or parental administration. As such apharmaceutical carrier, there may be mentioned, for example, a binder(syrup, Gum Arabic, gelatin, sorbitol, tragacanth, polyvinylpyrrolidone,etc.), an excipient (lactose, sugar, corn starch, potassium phosphate,sorbitol, glycine, etc.), a lubricant (magnesium steareate, talc,polyethylene glycol, silica, etc.), a disintegrator (potato starch,etc.) and a wetting agent (anhydrous lauryl sodium sulfate, etc.), andthe like.

Also, when these pharmaceutical preparations are administered orally,they may be a solid preparation such as tablets, granules, capsules,powders, or a liquid preparation such as solution, suspension, andemulsion. On the other hand, when they are administered parentally, forexample, they can be administered as an injection solution or aninfusion solution, using distilled water for injection, physiologicalsaline, aqueous glucose solution, etc., or they may be administered as asuppository, and the like.

A dose of the compound [I] or a pharmaceutically acceptable salt thereofof the present invention may vary depending on an administration method,an age, a body weight or a condition of a patient, etc., and, forexample, in case of oral administration, it is usually administered in adose of 0.1 to 20 mg/kg per day, and particularly preferably 0.1 to 10mg/kg per day, and in case of parental administration, usually in a doseof 0.01 to 10 mg/kg per day, particularly preferably 0.01 to 1 mg/kg perday.

[Method A]

-   -   The target compound [I] of the present invention can be        prepared, for example, by reacting the compound of the formula        [II]:    -   wherein Ring A represents an optionally substituted benzene        ring, R¹ is an optionally substituted alkyl group, an optionally        substituted hydroxyl group, a substituted thiol group, a        substituted carbonyl group, a substituted sulfinyl group, a        substituted sulfonyl group, or a group of the formula:    -   wherein R¹¹ and R¹² are the same or different and each is        hydrogen atom, a substituted carbonyl group, a substituted        sulfonyl group, an optionally substituted alkyl group or a        heterocyclic group containing 1 to 4 atom(s) selected from        nitrogen atom, oxygen atom and sulfur atom as a hetero atom,        wherein the heterocyclic group is optionally substituted, and        the nitrogen atom contained in the heterocyclic group is        optionally oxidized, or R¹¹ and R¹² are taken together, with an        adjacent nitrogen atom, to form a heterocyclic group selected        from piperidino group, azacycloheptyl group, pyrrolidino group,        thiazolidyl group, morpholino group, triazolyl group, tetrazolyl        group and purinyl group, wherein the heterocyclic group is        optionally substituted, and the nitrogen atom contained in the        heterocyclic group is optionally oxidized,    -   R² represents hydrogen atom, an optionally substituted hydroxyl        group, an optionally substituted amino group, an optionally        substituted alkyl group, a substituted carbonyl group or a        halogen atom,        with the compound of the formula [III]:    -   wherein Ring B represents an optionally substituted benzene        ring, R³ represents hydrogen atom or an optionally substituted        alkyl group, and R⁴ represents hydrogen atom or an optionally        substituted alkyl group,        in the presence of urea.        [Method B]

In the target compounds [I] of the present invention, the compound ofthe formula [I-a]:

-   -   wherein Ring A, Ring B, R², Z, R³ and R⁴ have the same meanings        as defined above,        can be prepared, for example, by reducing the compound of the        formula [IV]:    -   wherein Ring A, Ring B, R², Z, R³ and R⁴ have the same meanings        as defined above.        [Method C]

In the compounds of the present invention, the compound of formula[I-b]:

-   -   wherein Ring A, Ring B, R¹¹, R¹² R² Z, R³ and R⁴ have the same        meanings as defined above,        can be prepared by reacting the compound of the formula [IV]:    -   wherein Ring A, Ring B, R², Z, R³ and R⁴ have the same meanings        as defined above,        with the compound of the formula [V]:    -   wherein X¹ represents hydrogen atom, hydroxyl group, a silicon        atom, lithium atom or magnesium atom, R¹¹ and    -   R¹² have the same meaning as defined above.        [Method D]

In the compounds of the present invention, the compound of the formula[I-c]:

-   -   wherein Ring A, Ring B, R², Z, R³ and R⁴ have the same meanings        as defined above, and R¹³ represents an optionally substituted        carboxyl group,        can be prepared by reacting the compound of the formula [IV]:    -   wherein Ring A, Ring B, R², Z, R³ and R⁴ have the same meanings        as defined above,        with the compound of the formula [VI]:        X²CH₂R¹³   [VI]    -   wherein X² represents a leaving group, and R¹³ has the same        meaning as defined above,        and reducing the resulting compound of the formula[VII]:    -   wherein Ring A, Ring B, R¹³, Z, R², R³ and R⁴ have the same        meanings as defined above.        [Method E]

In the compounds of the present invention, the compound of the formula[I″]:

-   -   wherein Ring A, Ring B, R¹, R² and R⁴ have the same meanings as        defined above,        can be prepared by reacting the compound of the formula [II]:    -   wherein Ring A, R¹ and R² have the same meanings as defined        above,        with the compound of the formula [III′]:    -   wherein Ring B and R⁴ have the same meanings as defined above,        in the presence of an urea bond forming agent.

These [Method A] to [Method E] can be carried out as described bellow.

[Method A]

The reaction of the compound [II] with the compound [III] can be carriedout in a suitable solvent in the presence of an urea bond forming agent.The urea bond forming agent is exemplified by the compounds shown by theformula:

-   -   wherein W¹ and W² are the same or different, and each represents        a leaving group, and the like.    -   W¹ and W² are the same or different and each is exemplified by        an imidazolyl group, a halogen atom, phenoxy group and the like.        Specifically preferred are 1,1′-carbonyldiimidazole, a phosgene        and the like, and carbonyldihalides such as        1,1′-carbonyldiimidazole, a triphosgene or a phosgene etc. can        be used. Further, any solvent can be used as long as it does not        exert any bad effect on the reaction, for example, acetonitrile,        dichloromethane, tetrahydrofuran etc. can be used appropriately.        This reaction can proceed, for example, at 0° C. to 80° C.,        preferably at 0° C. to 50° C.

Further, in this reaction, the compound [I] can be prepared also byreacting the compound [II] with the urea bond forming agent of theformula:

-   -   wherein W¹ and W² are the same or different and each represents        a leaving group,        to give the resulting compound of the formula [VIII-a]:    -   wherein Ring A, R¹, R² and W² have the same meanings as above,        subsequently leading the compound [VIII-a] to a reactive        derivative thereof, and reacting the same with the compound        [III], or alternatively, the compound [I] can be prepared by        reacting the compound [III] and the urea bond forming agent of        the formula:    -   wherein W¹ and W² have the same meanings as defined above,        to give the resulting compound of the formula [VIII-b]:    -   wherein Ring B, R³, R⁴ and W² have the same meanings as defined        above,        subsequently leading the compound [VIII-b] to a reactive        derivative thereof, and reacting the same with the compound        [II].

As the reactive derivative, there are mentioned a compound in which W²is lead to a group as shown by the formula:

in the compound [VIII-a] or the compound [VIII-b], and the like.

The reaction of the compound [II] or the compound [III] with the urealinkage forming argent can proceed, for example, at 0° C. to 80° C.,preferably at 0° C. to 50° C. Further, any solvent can be used as longas it does not exert any bad effect on the reaction, for example,acetonitrile, dichloromethane, tetrahydrofuran, etc. can be usedappropriately.

The reaction to lead the compound [VIII-a] or the compound [VIII-b] to areactive derivative thereof can be carried out using aderivative-leading agent such as methyl iodide, for example, 0° C. to80° C., preferably at 0° C. to 50° C. Further, any solvent can be usedas long as it does not exert any bad effect on the reaction, forexample, acetonitrile, dichloromethane, tetrahydrofuran, etc. can beused appropriately.

The reaction of each reactive derivative with the compound [III] or thecompound [II] can be carried out in the presence of a base, for example,at 0° C. to 80° C., preferably at 0° C. to 50° C. Further, triethylamineetc. can be used as a base, and any solvent can be used as long as itdoes not exert any bad effect on the reaction, for example,acetonitrile, dichloromethane, tetrahydrofuran, etc. can be usedappropriately.

[Method B]

-   -   The reduction of the compound [IV] can be carried out in the        presence of a reductive agent in suitable solvent. As a        reductive agent, sodium borohydride and the like is preferred,        for example, sodium borohydride, aluminum hydride such as        diisobutyl aluminum hydride etc. can be used. Further, any        solvent can be used as long as it does not exert any bad effect        on the reaction, for example, ethanol, tetrahydrofuran,        dichloromethane, etc. can be used appropriately. This reaction        can be carried out, for example, at −70° C. to under reflux,        preferably, at −70° C. to 20° C.        [Method C]    -   The reaction of the compound [IV] with the compound [V] can be        carried out in a suitable solvent by subjecting the compounds to        a reductive amination reaction. This reductive amination        reaction can be carried out in acidic condition by hydrogenation        in the presence of a reductive agent such as sodium borohydride,        triacetoxysodium borohydride, sodium cyanoborohydride or a        reduction catalyst such as palladium. As the group [X¹] in the        compound [V], there are mentioned, for example, hydrogen atom,        hydroxyl group, silicon atom, lithium atom or magnesium atom,        and preferred are hydrogen atom and hydroxyl group. Any solvent        can be used as long as it does not exert any bad effect on the        reaction, for example, dichloromethane, acetic acid, ethanol,        methanol, etc. can be used appropriately. As a salt of the        compound [V], hydrochloride, acetate, etc. can be used        appropriately. The present reaction can proceed, for example, at        −10° C. to 80° C., preferably at 0° C. to 30° C.        [Method D]

The reaction of the compound [IV] with the compound [VI] can be carriedout optionally in the presence of a base in a suitable solvent. As theleaving group [X²] of the compound [VI], there are mentioneddiethylphosphono group, triphenylphophinyl group, etc. As the base,there are mentioned, for example, potassium-tert-butoxide,triethylamine, sodium hydroxide, etc., and preferred arepotassium-tert-butoxide, triethylamine, and the like. Further, anysolvent can be used as long as it does not exert any bad effect on thereaction, for example, tetrahydrofuran, dichloromethane, etc. can beused appropriately. The present reaction can proceed, for example, at−30° C. to 80° C., preferably at −20° C. to 30° C.

Further, the reduction of the compound [VII] can be carried out by aconventional method, by hydrogenation in the presence of a reductioncatalyst such as palladium, etc. As the solvent, methanol, ethanol, etc.can be used appropriately. The present reaction can proceed, forexample, at 0° C. to 50° C.

[Method E]

The reaction of the compound [II] with the compound [III′] can becarried out in the presence of a urea bond forming agent in a suitablesolvent. As the urea bond forming agent, those as shown by the formula:

-   -   wherein W¹ and W² are the same or different, and each represents        a leaving group.        As W¹ and W², being the same or different, there are mentioned        imidazolyl group, a halogen atom or phenoxy group and the like.        Specifically, 1,1′-carbonyldiimidazole, phosgene are preferred        and for example, carbonyldihalide such as        1,1′-carbonyldiimidazole, triphosgene, phosgene, etc. may be        used. Further, any solvent can be used as long as it does not        exert any bad effect on the reaction, for example, acetonitrile,        dichloromethane, tetrahydrofuran, etc. can be used        appropriately. The present reaction can proceed, for example, at        0° C. to 80° C., preferably at 0° C. to 50° C.

Further, the compound [I″] can be prepared by reacting the compound [II]with the urea bond forming agentof the formula:

-   -   wherein W¹ and W² are the same or different, and each represents        a leaving group,        to give the compound of the formula [VIII-a]:    -   wherein Ring A, R¹, R² and W² have the same meanings as defined        above,        subsequently leading the compound [VIII-a] to a reactive        derivative thereof, and reacting the same with the compound        [III′], or alternatively, the compound [I″] can be prepared by        reacting the compound [III′] with the urea bond forming agent of        the formula:    -   wherein W¹ and W² have the same meanings as defined above,        to give the compound of the formula [VIII′]:    -   wherein Ring B, R⁴ and W² have the same meanings as defined        above,        subsequently leading the compound [VIII′] to a reactive        derivative thereof, and reacting the same with the compound        [II].

As the reactive derivative, for example, the compound in which W² islead to the group as shown by the formula:

in the compound [VIII-a] or the compound [VIII′].

The reaction of the compound [II] or the compound [III′] with a ureabond forming agent can proceed, for example, at 0° C. to 80° C.,preferably at 0° C. to 50° C. Further, any solvent can be used as longas it does not exert any bad effect on the reaction, for example,acetonitrile, dichloromethane, tetrahydrofuran, etc. can be usedappropriately.

The reaction to lead the compound [VIII-a] or the compound [VIII′] to areactive derivative thereof can be carried out using aderivative-leading agent such as methyl iodide, for example, 0° C. to80° C., preferably at 0° C. to 50° C. Further, any solvent can be usedas long as it does not exert any bad effect on the reaction, forexample, acetonitrile, dichloromethane, tetrahydrofuran, etc. can beused appropriately.

The reaction of each reactive derivative with the compound [III] or thecompound [II] can be carried out in the presence of a base, for example,at 0° C. to 80° C., preferably at 0° C. to 50° C. Further, triethylamineetc. can be used as a base, and any solvent can be used as long as itdoes not exert any bad effect on the reaction, for example,acetonitrile, dichloromethane, tetrahydrofuran, etc. can be usedappropriately.

The compound [I] of the present invention can be also prepared byconverting the group R¹ and group R³ of the compound obtained in theabove described method, to a desired substituent. Method for conversionof the, substituents can be appropriately selected, depending on kindsof desired substituents, and the following (method a) to (method q) canbe employed.

(Method A)

The compound [I] in which R¹ is a group comprising a substitutedhydroxyl group (for example, an optionally substituted alkoxy group, asubstituted carbonyloxy group or alkylsulfonyloxy group, etc.) in theformula [I] can be prepared by subjecting the corresponding compoundhaving hydroxyl group as R¹ to alkylation, acylatoin or sulfonylation bya conventional method. For example, alkylation can proceed at −10° C. to80° C., acylatoin can proceed at 5° C. to 80° C., and sulfonylation canproceed at 5° C. to 80° C.

(Method B)

The compound [I] in which R¹ is a group comprising a substituted aminogroup in the formula [I] can be prepared by substituting thecorresponding compound having an amino group as R¹ with substituent(s)of the amino group by a conventional method (for example, analkoxycarbonyl group such as tert-butoxycarbonyl, an arylalkoxycarbonylgroup such as benzyloxycarbonyl group, etc., an alkanoyl group such asformyl group, acetyl group, propionyl group, etc., an alkyl group suchas methyl group, ethyl group, propyl group, etc., an alkylsulfonyl groupsuch as methanesulfonyl group, ethanesulfonyl group, etc., analkenylsulfonyl group such as vinylsulfonyl group, etc., a heterocyclicgroup such as pyridyl group, etc., etc.). Alternatively, it can beprepared by using a carbamate synthesizing reagent such asN,N′-succinimidylcarbonate, etc., by reacting with, for example, analkoxyalkylalcohol, etc. Substitution can be suitably carried out by aconventional method, depending on the kinds of the substituent, byalkylation, acylation, sulfonylation, arylatoin, etc. Further, bysubstituting the hydrogen atom on the amino group, it can be made into adi-substituted compound. The present reaction can proceed at −20° C. to50° C.

Further, in case that the compound [I] in which R¹ is a group comprisinga substituted amino group has a urea bond, it can be prepared byreacting the corresponding amine compound and a urea bond forming agent,according to the same manner as in [method A] or, a method described inJapanese Provisional Patent Publication No. 10-195037.

Further, the compound [I] in which R¹ is a group comprising asubstituted amino group in the formula [I] can be prepared by adding anamino group-containing compound to the corresponding compound having acarbon-carbon double bond at R¹. The present reaction can be carried outby refluxing a solvent under heating, or in the absence of a catalyst.

(Method C)

The compound [I] in which R¹ is a group comprising an amino group in theformula [I] can be prepared by removing a protective group from thecorresponding compound having a protected amino group at R¹. Removal ofthe protecting group can be carried out by a conventional method (forexample, acid treatment, base treatment, catalytic reduction, etc.). Inthe present reaction, a reaction by acid treatment can proceed at 5° C.to 120° C., a reaction by base treatment can proceed at 5° C. to 40° C.,and a reaction by catalytic reduction can proceed at 10° C. to 40° C.

Further, the compound [I] in which R¹ is a group comprising an aminogroup in the formula [I] can be prepared by reducing the correspondingcompound having a nitro group at R¹. Reduction can be carried out, inthe presence of an acid, by reacting tin chloride, zinc, etc. Forexample, the present reaction can be carried out while refluxing thesolvent under heating.

Further, the compound [I] in which R¹ is a group comprising an aminogroup in the formula [I] can be prepared by subjecting the correspondingcompound having a carboxyl group at R¹ to Curtius rearrangement, etc.Curtius rearrangement can be carried out, for example, according to themethod described in Advanced Organic Chemistry, vol.4, page 1054. Thatis, it can be carried out by converting a carboxyl group into an acidchloride by thionyl chloride, etc, and subsequently, subjecting the sameto azidation by sodium azide, etc., followed by hydrolysis.

(Method D)

The compound [I] in which R¹ is a group comprising hydroxyl group in theformula [I] can be prepared by removing a protective group from thecorresponding compound having a protected hydroxyl group at R¹ by aconventional method. Removal of the protecting group can be carried outby acid treatment, base treatment, catalytic reduction, etc. dependingon the kinds of the protecting group. The present reaction can proceed,for example, at 0° C. to 80° C., particularly preferably at 5° C. to 50°C.

Further, the compound [I] in which R¹ is a group comprising hydroxylgroup in the formula [I] can be prepared by reducing the correspondingcompound having a formyl group at R¹. Reduction can be carried out byreacting the compound in the presence of a reductive agent such assodium borohydride, etc. The present reaction can proceed, for example,at −80° C. to 80° C., particularly preferably at −70° C. to 20° C.

Further, the compound [I] in which R¹ is a group comprising hydroxylgroup in the formula [I] can be prepared by reducing the correspondingcompound having an ester or a carboxyl group at R¹. Reduction can becarried out by reacting the compound in the presence of a reductiveagent such as lithium aluminum hydride, etc. The present reaction canproceed, for example, at −50° C. to 200° C., particularly preferably at−20° C. to 60° C.

(Method E)

In case that R¹ in the formula [I] is hydroxyl group and it has anasymmetric center at the bonding portion, the configuration of thecompound can be converted to the opposite configuration, for example,according to a method of Mitsunobu, et al. as described in Synthesis,pages 1 to 28, 1981. Specifically, conversion can be carried out byreacting the compound in the presence of triphenylphosphine, benzoicacid and diethylazodicarboxylate, in a suitable solvent. The presentreaction can proceed, for example, at 0° C. to 60° C., particularlypreferably at 5° C. to 40° C.

(Method F)

The compound [I] in which R¹ is a group comprising an optionallysubstituted thiol group in the formula [I] can be prepared by reactingthe corresponding compound having hydroxyl group at R¹ with thecorresponding compound comprising a thiol group, for example, accordingto a method of Mitsunobu, et al. as described in Synthesis, pages 1 to28, 1981. Specifically, reaction can be carried out by reacting thecompound in the presence of triphenylphosphine, anddiethylazodicarboxylate, in a suitable solvent. The present reaction canproceed, for example, while refluxing a solvent under heating.

The compound [I] in which R¹ is a group comprising an optionallysubstituted thiol group in the formula [I] can be prepared by reactingthe corresponding compound [I] having a halogen atom at R¹ with thecorresponding compound comprising a thiol group. The present reactioncan proceed, for example, at −50° C. to 150° C., particularly preferablyat 10° C. to 100° C.

Still further, the compound [I] in which R¹ is a group comprising analkylthio group can be prepared by subjecting the corresponding compound[I] having a thiol group at R¹or the corresponding compound having aprotective thiol group (for example, an acetylated thiol group) toalkylation. The present reaction can proceed in the presence of a base,for example, at −10° C. to 80° C., particularly preferably at 5° C. to50° C.

(Method G)

The compound [I] in which R¹ in the formula [I] is a group comprising asubstituted amino group can be prepared by subjecting the correspondingcompound [I] having hydroxyl group at R¹ to amination, for example,according to a method of Mitsunobu, et al. as described in Synthesis,pages 1 to 28, 1981.

(Method H)

The compound [I] in which R¹ in the formula [I] is a group comprising afree carboxyl group can be prepared by subjecting the correspondingcompound [I] having an esterificated carboxyl group at R¹ todeesterification, according to the conventional method (for example, byhydrolysis with a base such as sodium hydroxide, etc., acid treatmentwith hydrogen chloride, hydrogen bromide, etc., reduction under hydrogenatmosphere using palladium (black), palladium carbon, etc., depending onthe kinds of the ester residue). In the deesterification reaction, forexample, hydrolysis with a base can proceed, at 5° C. to 70° C., acidtreatment can proceed at 5° C. to 80° C., reduction can proceed at 10°C. to 40° C.

(Method I)

The compound [I] in which R¹ in the formula [I] is a group comprising anamido bond can be prepared by reacting the corresponding compound [I]having a free carboxyl group at R¹with the corresponding amine compound,or by reacting the corresponding compound [I] having a free amino groupat R¹ with the corresponding carboxylic acid compound, in the presenceor in the absence of a condensing agent. As the condensing agent, thereare used 1,1′-carbonyldiimidazole, 1,3-dicyclohexylcarbodiimide,1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, isobutylchloroformate or N-methylmorpholine, etc., which are normally used in areaction to form an amide bond from a carboxylic acid and an amine. Thepresent reaction can proceed, for example, at −20° C. to 50° C.

(Method J)

The compound [I] in which R¹ in the formula [I] is a group comprising aheterocyclic group whose nitrogen atom is substituted by an oxo group (anitrogen atom is oxidized) (for example, N-oxomorpholino group, etc.)can be prepared by treating the corresponding compound [I] having aheterocyclic group at R¹ with an oxidizing agent (forexample,3-chloroperbenzoic acid, hydrogen peroxide, peracetic acid,oxone, etc.). The present reaction can proceed, for example, at 5° C. to50° C.

(Method K)

The compound [I] in which R¹ in the formula [I] is a group comprising aheterocyclic group whose nitrogen atom is oxidized, other than thecompound of the above (method j) (for example, N-alkyl-4-morpholinogroup, etc.) can be prepared by reacting the corresponding compound [I]having a heterocyclic group at R¹ with an alkyl halide. The presentreaction can proceed, for example, at 20° C. to 80° C.

(Method 1)

The compound [I] in which R³ in the formula (I) is an alkyl group can beprepared by subjecting the corresponding compound [I] in which R³ ishydrogen atom to alkylation by a conventional method. The alkyl groupmay be substituted. The present reaction can proceed, for example, at20° C. to 80° C.

(Method M)

The compound [I] in which R¹ in the formula [I] is a group comprising agroup whose sulfur atom is mono-substituted by an oxo group (forexample, a sulfinyl group, etc.) can be prepared by treating thecorresponding compound [I] having a thio group at R¹ with an oxidizingagent (for example, 3-chloroperbenzoic acid, peracetic acid, sodiumperiodate, oxone, etc.). The present reaction can proceed, for example,at −80° C. to 150° C., particularly preferably at 0° C. to 40° C.

(Method N)

The compound [I] in which R¹ in the formula [I] is a group comprising agroup whose sulfur atom is di-substituted by oxo groups (for example, asulfonyl group, etc.) can be prepared by treating the correspondingcompound [I] having a thio group at R¹ with an oxidizing agent (forexample, 3-chloroperbenzoic acid, peracetic acid, sodium periodate,oxone, etc.). The present reaction can proceed, for example, at −80° C.to 150° C., particularly preferably at 0° C. to 40° C.

(Method O)

The compound [I] in which R¹ in the formula [I] is a group comprising anamino group can be prepared by subjecting the corresponding compound [I]having a carbonyl group at R¹ to reductive amination. The presentreaction can be carried out in the same manner as in [Method C]mentioned above.

(Method P)

The compound [I] in which R¹ in the formula [I] is a group comprising asulfinic acid can be prepared by reacting the corresponding compound [I]having an alkylsulfinyl group at R¹, for example, according to a methoddescribed in Synlett, April, pages 375 to 377, 1997.

(Method Q)

The compound [I] in which R¹ in the formula [I] is a group comprising animidazolidinyl group or a hexahydropyrimidinyl group can be prepared bysubjecting the corresponding compound [I] having an aminoalkylaminogroup at R¹ to cyclization, for example, in the presence of a condensingagent such as a 1,1′-carbonyldiimidazole, etc. The present reaction canproceed, for example, at −20° C. to 50° C.

As the solvents to be used in the reactions described in the above(method a) to (method q), any solvent can be used as long as it does notaffect the reaction, for example, those can be used by appropriatelyselecting from dioxane, ethylene glycol dimethylether,dimethylacetamide, dimethylformamide, hexamethylphosphoramide, benzene,tetrahydrofuran, toluene, ethyl acetate, an alcohol, dichloromethane,carbon tetrachloride, 1,3-dimethyl-2-imidazolidine, acetic acid, diethylether, methoxyethane, dimethylsulfoxide, acetonitrile, water and themixture thereof.

Incidentally, the compound [IV] as the starting material in the presentinvention is a novel compound, and it can be prepared, for example, asshown in the chemical formula below:

wherein R⁵¹ represents an alkyl group, R⁶¹ represents a protecting groupfor an amino group, R⁵² represents an alkyl group which may form a bondat a terminal thereof, X³ represents a leaving group, X⁴ represents aleaving group, and Ring A, Ring B, R³and R⁴ have the same meanings asdefined above.

That is, pyridine compound [IX] and Grignard compound [X] are subjectedto a condensation reaction, and further, an amino group is protected, togive a compound [XI]. Subsequently, it is subjected to a reductionreaction, to give a compound [XII]. Further, a carbonyl group of thecompound [XII] is protected by a ketal, to prepare a compound [XIII],the protecting group for the amino group is removed, to give a compound[XIV]. Subsequently, the compound [XIV] and the compound [XV] aresubjected to a condensation reaction, to give a compound [XVI], followedby reacting the same with a compound [XVII], or the compound [XIV] andthe compound [III] are subjected to a condensation reaction, to give acompound [XVIII], and by removing the protecting group thereof, to givea compound [IV].

The compound [IV] has an asymmetric carbon, therefore, optical isomersare present based on the asymmetric carbon. By using an optical isomerof the above described compound [XIV], a desired optical isomer of thecompound [IV] can be prepared.

The optical isomer of the compound [XIV] can be prepared by subjectingthe racemic mixture of the compound [XIV] to an optical resolution by aconventional method. The optical resolution can be carried out, forexample, by reacting the compound [XIV] with N-acyl-optically activeamino acid or N-sulfonyl-optically active amino acid, to give two kindsof diastereomeric salts, and by separating and collecting one of thediastereomeric salts, using a difference in solubilities thereof.

The acyl group of N-acyl-optically active amino acid is exemplified byacetyl group, propionyl group, tosyl group or benzyloxycarbonyl group,and the optically active amino acid is exemplified by L-phenylalanine,L-leucine, L-glutamine, L-methionine, L-valine, L-threonine,D-phenylalanine or D-phenylglycine.

Further, the compound [II] as the starting material in the presentinvention is a novel compound, and it can be prepared, for example, asshown in the chemical formula below:

wherein Ring A, R¹¹, R¹², R⁶¹ and X¹ have the same meanings as definedabove.

That is, the compound [XII] and the compound [V] are subjected to areductive amination, to give a compound [XIX], and by removing theprotecting group of the amino group thereof, a compound [II-a] isprepared. Reductive amination can be carried out in the same manner asin [Method C].

In preparing the above compound [IV], each of the intermediate compoundsare not limited to those as shown in the reaction formula, and a saltthereof or a reactive derivative thereof may be suitably used, as longas it does not affect the reaction.

Further, in the starting material [II] of the present invention, thecompound [II-b] can be prepared, for example, as shown in the chemicalformula below:

wherein R⁵³ represents an alkyl group, X³ represents a halogen atom andRing A has the same meaning as defined above.

That is, pyridine compound [XX] and the compound [XXI] are condensed,and the resulting compound [XXII] is reduced, to give a compound [II-b].

Further, in the starting materials of the present invention, thecompound of the formula [II-c]:

wherein a symbol has the same meaning as defined above, can be preparedas shown below.

wherein symbols have the same meanings as defined above.

That is, the compound [XII] is reduced, to give a compound [XXIII], anddeprotection of the amino group of the obtained compound [XXIII] iscarried out to give the compound [II-c].

Although there are optical isomers of the compound [II-c], in thesimilar method as in the above mentioned optical resolution for thecompound [XIV], it can be prepared by optical resolution from a racemicmixture.

Further, in preparation of the compound or the starting materials of thepresent invention, when the starting materials or the intermediates havea functional group, suitable protecting groups can be introduced to eachof the functional group, by a conventional method, besides the abovedescribed method, and if they are not necessary, these protecting groupscan be suitably removed.

In the present specification, the alkyl group means, for example, astraight or branched alkyl group having 1 to 6 carbon atoms such asmethyl group, ethyl group, propyl group, butyl group, isobutyl group,tert-butyl group, isopentyl group, etc., preferably those having 1 to 4carbon atoms. The alkenyl group means, for example, a straight orbranched alkenyl group having 2 to 7 carbon atoms such as vinyl group,aryl group, propenyl group, isopropenyl group, etc., preferably thosehaving 1 to 4 carbon atoms. The alkoxy group means a straight orbranched alkoxy group having 1 to 6 carbon atoms such as methoxy group,ethoxy group, propoxy group, isopropoxy group, butoxy group, etc.,preferably those having 1 to 4 carbon atoms. The alkanoyl group means astraight or branched alkanoyl group having 1 to 6 carbon atoms such asformyl group, acetyl group, propionyl group, butyryl group, valerylgroup, tert-butylcarbonyl group, etc., preferably those having 1 to 4carbon atoms. The cyclic lower alkyl group means a cycloalkyl grouphaving 3 to 8 carbon atoms such as cyclopropyl group, cyclobutyl group,cyclopentyl group, cyclohexyl group, cycloheptyl group, cyclooctylgroup, etc., preferably tose having 3 to 6 carbon atoms. Further, thehalogen atom is exemplified by chlorine atom, bromine atom, fluorineatom and iodine atom.

EXAMPLES

In the following, the present invention will be explained in more detailby referring to Examples and Reference Examples, but the presentinvention is not limited by these Examples.

Example 1

(1) In 30 ml of methanol was dissolved 1.43 g of1-{N-(3,5-bistrifluoromethylbenzyl)-N-methyl}aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-oxopiperidine,and 114 mg of sodium borohydride was added thereto. The mixture wasstirred at room temperature for 3 hours. To the reaction mixture wereadded an aqueous ammonium chloride solution and ethyl acetate, and afterstirring the mixture, layers were separated. The organic layer waswashed with water and brine and dried, and then, the solvent was removedby distillation under reduced pressure. The residue was purified bysilica gel column chromatography (chloroform:acetone=4:1), to give 0.99g of1-{N-(3,5-bistrifluoromethylbenzyl)-N-methyl}aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-hydroxypiperidineas shown in Table 1 below.

(2) 200 mg of the compound of the above (1) was further purified bysilica gel column chromatography (hexane:ethyl acetate=4:1), to give 18mg of (a)trans-1-{N-(3,5-bistrifluoromethylbenzyl)-N-methyl}aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-hydroxypiperidineand 125 mg of (b)cis-1-{N-(3,5-bistrifluoromethylbenzyl)-N-methyl}aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-hydroxypiperidineas shown in Table 1 below.

Example 2

In 10 ml of tetrahydrofuran was dissolved 200 mg of(2R)-1-[N-(1-(S)-(3,5-bistrifluoromethylphenyl)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-oxopiperidine,and 60 mg of sodium borohydride was added thereto and the mixture wasrefluxed. While continuously refluxing the mixture, a mixed solvent of 1ml of methanol and 5 ml of tetrahydrofuran was added thereto dropwise.After 5 hours, the reaction mixture was poured into water and layerswere separated. The aqueous layer was extracted with ethyl acetate, andthe combined organic layers were washed with water and saturated brineand dried, and then, the solvent was removed by distillation underreduced pressure. The residue was purified by silica gel columnchromatography (hexane:ethyl acetate=1:1→1:2), to give 33 mg of (a)(2R,4R)-1-[N-{1-(S)-(3,5-bistrifluoromethylphenyl)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-hydroxypiperidineand 160 mg of (b)(2R,4S)-1-[N-{1-(S)-(3,5-bistrifluoromethylphenyl)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-hydroxypiperidineas shown in Table 2 below.

Example 3

(2R)-1-[N-(3,5-bistrifluoromethylbenzyl)-N-methyl]aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-oxopiperidinewas used and treated in the same manner as in Example 2 to give (a)(2R,4R)-1-{N-(3,5-bistrifluoromethylbenzyl)-N-methyl}aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-hydroxypiperidineand (b)(2R,4S)-1-{N-(3,5-bistrifluoromethylbenzyl)-N-methyl}aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-hydroxypiperidineas shown in Table 2 below.

Example 4

In 5 ml of dimethylformamide was dissolved 150 mg of1-{N-(3,5-bistrifluoromethylbenzyl)-N-methyl}aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-hydroxypiperidine,and 40 mg of sodium hydride (60%) was added thereto at 0° C. To thissolution, 0.2 ml of methyl iodide was added at 0° C., and the mixturewas stirred at room temperature for 16 hours. After water and ethylacetate were added to this solution, and the mixture was stirred, layerswere separated. The organic layer was washed with water, dried overmagnesium sulfate, and concentrated under reduced pressure. Theconcentrated residue was purified by silica gel column chromatography(hexane:ethyl acetate=2:1), to give 72 mg of (a)cis-1-{N-(3,5-bistrifluoromethylbenzyl)-N-methyl}aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-methoxypiperidineand 36 mg of (b)trans-1-{N-(3,5-bistrifluoromethylbenzyl)-N-methyl}aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-methoxypiperidineas shown in Table 3 below.

Example 5

1-{N-(3,5-bistrifluoromethylbenzyl)-N-methyl}aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-hydroxypiperidineand 2-picolyl chloride hydrochloride were used and treated in the samemanner as in Example 4 above, to give1-{N-(3,5-bistrifluoromethylbenzyl)-N-methyl}aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-(2-pyridylmethoxy)piperidineas shown in Table 4 below.

Example 6

In 2 ml of a toluene solution containing 98 mg of1-{N-(3,5-bistrifluoromethylbenzyl)-N-methyl}aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-hydroxypiperidinewere added 57.6 mg of dimethylaminoethyl chloride hydrochloride, 12.5 mgof tetrabutylammonium bromide and 1 ml of 10M aqueous sodium hydroxidesolution at room temperature. After stirring the mixture at roomtemperature for 2 hours, stirring was further carried out at 60° C. for16 hours. After completion of the reaction, ethyl acetate and an aqueoussodium hydrogen carbonate solution were added to the reaction mixtureand layers were separated. The organic layer was further washed withwater, dried over magnesium sulfate, and concentrated under reducedpressure. The residue was purified by silica gel column chromatography(chloroform:methanol=19:1). The obtained oily substance was treated with4M hydrochloric acid-ethyl acetate solution. The formed precipitateswere collected by filtration and dried to give 53 mg of1-{N-(3,5-bistrifluoromethylbenzyl)-N-methyl}aminocarbonyl-4-(1-dimethylaminoethoxy)-2-(4-fluoro-2-methylphenyl)piperidinehydrochloride as shown in Table 4 below.

Example 7

1-(2-chloroethyl)piperidine hydrochloride and1-{N-(3,5-bistrifluoromethylbenzyl)-N-methyl}aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-hydroxypiperidinewere treated in the same manner as in Example 6, to give1-{N-(3,5-bistrifluoromethylbenzyl)-N-methyl}aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-(1-piperidylethoxy)piperidinehydrochloride as shown in Table 4 below.

Example 8

In 3 ml of dichloromethane was dissolved 100 mg of1-{N-(3,5-bistrifluoromethylbenzyl)-N-methyl}aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-oxopiperidine,and added thereto were 0.03 ml of piperidine and 0.018 ml of aceticacid, and the mixture was stirred. 129.7 mg of sodium triacetoxyborohydride was added thereto and the mixture was stirred at roomtemperature for 12 hours. The reaction mixture was poured into asaturated aqueous sodium bicarbonate solution, layers were separated andthe aqueous layer was extracted with dichloromethane. The combinedorganic layers were washed with water and brine, dried and the solventwas removed by distillation under reduced pressure. Subsequently, theresidue was purified by NH silica gel column chromatography(hexane:ethyl acetate=4:1), to givetrans-1-{N-(3,5-bistrifluoromethylbenzyl)-N-methyl}aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-piperidinopiperidineandcis-1-{N-(3,5-bistrifluoromethylbenzyl)-N-methyl}aminocarbonyl-2-(4-fluoro2-methylphenyl)-4-piperidinopiperidine. Each of the obtained compoundswas dissolved in 1 ml of chloroform, respectively, and 0.2 ml of 4Mhydrochloric acid-ethyl acetate solution was added thereto. Afterstirring the mixture for a while, the mixture was concentrated underreduced pressure to give 58 mg of (a)trans-1-{N-(3,5-bistrifluoromethylbenzyl)-N-methyl}aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-piperidinopiperidinehydrochloride and 16 mg of (b)cis-1-{N-(3,5-bistrifluoromethylbenzyl)-N-methyl}aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-piperidinopiperidinehydrochloride as shown in Table 5 below.

Examples 9 to 44

The corresponding starting materials were used and treated in the samemanner as in Example 8, to give compounds as shown in Tables 6 to 18below.

Example 45

In 20 ml of acetic acid was dissolved 2.45 g of1-{N-(3,5-bistrifluoromethylbenzyl)-N-methyl}aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-oxopiperidine,and 3.85 g of ammonium acetate and 5 g of sodium sulfate were addedthereto. The mixture was stirred at room temperature for an hour.Subsequently, 1.18 g of sodium triacetoxy borohydride was added theretoand the mixture was stirred at room temperature for 24 hours. After thereaction was completed, a 2M aqueous sodium carbonate solution,chloroform and water were added thereto. The mixture was stirred for 0.5hours, and layers were separated. The aqueous layer was extracted againby chloroform and combined organic layer was dried over sodium sulfateand concentrated under reduced pressure. The residue was purified bysilica gel column chromatography (chloroform:methanol=10:1). Theobtained oily substance was treated with 4M hydrochloric acid-ethylacetate solution, and concentrated under reduced pressure. Subsequently,the concentrate was triturated by isopropyl ether, to give 1.16 g of4-amino-1-{N-(3,5-bistrifluoromethylbenzyl)-N-methyl}aminocarbonyl-2-(4-fluoro-2-methylphenyl)piperidinehydrochloride as shown in Table 19 below.

Example 46

(2R)-1-{N-(3,5-bistrifluoromethylbenzyl)-N-methyl}aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-oxopiperidinewas used and treated in the same manner as in Example 45, to give(2R)-4-amino-1-{N-(3,5-bistrifluoromethylbenzyl)-N-methyl}aminocarbonyl-2-(4-fluoro-2-methylphenyl)piperidinehydrochloride as shown in Table 19 below.

Example 47

In 20 ml of a dichloromethane solution containing 1.06 g of4-amino-1-{N-(3,5-bistrifluoromethylbenzyl)-N-methyl}aminocarbonyl-2-(4-fluoro-2-methylphenyl)piperidinewere added 0.42 ml of triethylamine and 660 mg of dibutyloxycarbonate,and the mixture was stirred at room temperature for 16 hours. Thereaction mixture was concentrated under reduced pressure, and theresidue was purified by silica gel column chromatography (hexane:ethylacetate=4:1), to give 130 mg of (a)trans-1-{N-(3,5-bistrifluoromethylbenzyl)-N-methyl}aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-tert-butoxycarbonylaminopiperidineand 120 mg of (b)cis-1-{N-(3,5-bistrifluoromethylbenzyl)-N-methyl}aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-tert-butoxycarbonylaminopiperidineas shown in Table 20 below.

Example 48

100 mg oftrans-1-{N-(3,5-bistrifluoromethylbenzyl)-N-methyl}aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-tert-butoxycarbonylaminopiperidinewas treated with 4M hydrochloric acid-ethyl acetate solution. Ether andhexane were added thereto and formed precipitates were collected byfiltration, washed with hexane and vacuum dried, to give 56 mg oftrans-4-amino-1-{N-(3,5-bistrifluoromethylbenzyl)-N-methyl}aminocarbonyl-2-(4-fluoro-2-methylphenyl)piperidinehydrochloride as shown in Table 21 below.

Example 49

cis-1-{N-(3,5-bistrifluoromethylbenzyl)-N-methyl}aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-tert-butoxycarbonylaminopiperidine was used and treated in the samemanner as in Example 48, to givecis-4-amino-1-{N-(3,5-bistrifluoromethylbenzyl)-N-methyl}aminocarbonyl-2-(4-fluoro-2-methylphenyl)piperidinehydrochloride as shown in Table 21 below.

Example 50

In 1.2 ml of dichloromethane was dissolved 60 mg of4-amino-1-{N-(3,5-bistrifluoromethylbenzyl)-N-methyl}aminocarbonyl-2-(4-fluoro-2-methylphenyl)piperidine,and added thereto were 0.02 ml of triethylamine and 0.013 ml ofpropionyl chloride under ice-cooling, and the mixture was stirred underice-cooling for 20 minutes. The reaction mixture was poured intosaturated brine and layers were separated. The aqueous layer wasextracted with dichloromethane and the combined organic layers werewashed with brine, dried and the solvent was removed by distillation.The residue was purified by thin-layer silica gel chromatography(chloroform:methanol=9:1), to give 40 mg of (a)trans-1-{N-(3,5-bistrifluoromethylbenzyl)-N-methyl}aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-propionylaminopiperidineand 27 mg of (b)cis-1-{N-(3,5-bistrifluoromethylbenzyl)-N-methyl}aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-propionylaminopiperidineas shown in Table 22 below.

Examples 51 to 69

The corresponding starting materials were used and treated in the samemanner as in Example 50 to give compounds as shown in Tables 23 to 33below.

Example 70

In 4 ml of a dichloromethane solution containing 98 mg of4-amino-1-{N-(3,5-bistrifluoromethylbenzyl)-N-methyl}aminocarbonyl-2-(4-fluoro-2-methylphenyl)piperidinewere added 0.056 ml of triethylamine and 0.028 ml of acetyl chloridesuccessively at 0° C., and the mixture was stirred at 0° C. for 0.5hours. After the reaction was completed, an aqueous sodium hydrogencarbonate solution and chloroform were added thereto and the mixture wasstirred and layers were separated. The aqueous layer was extracted againwith chloroform, and the combined organic layers were dried overmagnesium sulfate and concentrated under reduced pressure. The residuewas purified by silica gel column chromatography (chloroform:ethylacetate=4:1) and vacuum dried to give 86 mg of4-acetylamino-1-{N-(3,5-bistrifluoromethylbenzyl)-N-methyl}aminocarbonyl-2-(4-fluoro-2-methylphenyl)piperidinein powder form as shown in Table 34 below.

Example 71

4-Amino-1-{N-(3,5-bistrifluoromethylbenzyl)-N-methyl}aminocarbonyl-2-(4-fluoro-2-methylphenyl)piperidineand nicotinic chloride hydrochloride were used and treated in the samemanner as in Example 70, to give1-{N-(3,5-bistrifluoromethylbenzyl)-N-methyl}aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-(3-pyridylcarbonylamino)piperidineas shown in Table 34 below.

Example 72

To 3 ml of a dimethylformamide solution containing 124 mg of4-amino-1-{N-(3,5-bistrifluoromethylbenzyl)-N-methyl}aminocarbonyl-2-(4-fluoro-2-methylphenyl)piperidinewere added 44 mg of N-tert-butoxycarbonyl glycine, 58 mg of1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and 13.5 mgof 1-hydroxy-1H-benzotriazol, and the mixture was stirred at roomtemperature for 16 hours. After the reaction was completed, an aqueoussodium hydrogen carbonate solution and chloroform were added thereto andthe mixture was stirred and layers were separated. The aqueous layer wasextracted again with chloroform, and the combined organic layers weredried over magnesium sulfate and concentrated under reduced pressure.The residue was purified by silica gel column chromatography(chloroform:methanol=19:1), and treated with 4M hydrochloric acid-ethylacetate solution. The mixture was concentrated under reduced pressure.The formed precipitates were washed with isopropyl ether, collected byfiltration and vacuum dried to give 83 mg of4-aminoacetylamino-1-{N-(3,5-bistrifluoromethylbenzyl)-N-methyl}aminocarbonyl-2-(4-fluoro-2-methylphenyl)piperidinehydrochloride as shown in Table 35 below.

Example 73

4-Amino-1-{N-(3,5-bistrifluoromethylbenzyl)-N-methyl}aminocarbonyl-2-(4-fluoro-2-methylphenyl)piperidineand N,N-dimethyl glycine were used and treated in the same manner as inExample 72, to give1-{N-(3,5-bistrifluoromethylbenzyl)-N-methyl}aminocarbonyl-4-dimethylaminoacetylamino-2-(4-fluoro-2-methylphenyl)piperidinehydrochloride as shown in Table 35 below.

Example 74

To 25 ml of an ethanol solution containing 320 mg ofcis-1-{N-(3,5-bistrifluoromethylbenzyl)-N-methyl}aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-(4-nitrobenzoyl)aminopiperidinewas added 480 mg of tin dichloride, and the mixture was refluxed for 4hours. After the reaction was completed, ethanol was removed bydistillation under reduced pressure. Added thereto were diethyl etherand an aqueous 2M sodium hydroxide solution and layers were separated.The organic layer was washed again with 2M aqueous sodium hydroxidesolution and further washed with water. This organic layer was driedover magnesium sulfate and concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography(chloroform:methanol=19:1), and the obtained oily substance was treatedwith 4M hydrochloric acid-ethyl acetate solution. The reaction mixturewas concentrated under reduced pressure and triturated by isopropylether, to give 152 mg ofcis-4-(4-aminobenzoyl)amino-1-{N-(3,5-bistrifluoromethylbenzyl)-N-methyl}aminocarbonyl-2-(4-fluoro-2-methylphenyl)piperidinehydrochloride as shown in Table 36 below.

Example 75

To 60 ml of a tetrahydrofuran solution containing 3.91 g ofN-{1-(R)-(3,5-bistrifluoromethylphenyl)ethyl)-N-methylamine was added2.34 g of 1,1′-carbonyldiimidazole, and the mixture was stirred at 40°C. overnight. After the solvent was removed by distillation, ethylacetate was added. The whole organic layers were washed with water andsaturated brine, and dried. The white crystals obtained by removing thesolvent by distillation under reduced pressure were collected bydiisopropyl ether. The obtained white crystals were dissolved in 60 mlof acetonitrile, and 3.5 ml of methyl iodide was added thereto. Afterthe reaction proceeded at 60° C. for 2 hours, the solvent was removed bydistillation under reduced pressure. 224 mg of the residue was dissolvedin 2 ml of dichloromethane, and under ice-cooling, 100 mg ofcis-2-(4-fluoro-2-methylphenyl)-4-(propanoylamino)piperidine and 0.11 mlof triethylamine were added thereto and the mixture was stirred at roomtemperature overnight. The reaction mixture was poured into water, andlayers were separated. The aqueous layer was extracted withdichloromethane, and the combined organic layers were washed with waterand saturated brine and dried, and the solvent was removed bydistillation under reduced pressure. The residue was purified by silicagel column chromatography (hexane:ethyl acetate=1:3), to give 83.5 mg of(2R,4S)-1-[N-{1-(R)-(3,5-bistrifluoromethylphenyl)ethyl)-N-methyl]aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-propanoylaminopiperidineas shown in Table 37 below.

Examples 76 to 84

The corresponding starting materials were used and treated in the samemanner as in Example 75 to give compounds as shown in Tables 37 to 39below.

Example 85

To 1 ml of an ethyl acetate solution containing 212 mg of(2R,4S)-1-[N-{1-(R)-(3,5-bistrifluoromethylphenyl)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-tert-butoxycarbonylaminopiperidinewas added 2 ml of 4M hydrochloric acid-ethyl acetate solution underice-cooling, and the mixture was stirred under ice-cooling for 30minutes. After the solvent was removed by distillation under reducedpressure, chloroform and 2M aqueous sodium hydroxide solution were addedto the residue. Layers were separated and the aqueous layer wasextracted with chloroform and the combined organic layers were dried andthe solvent was removed by distillation under reduced pressure, to give177 mg of(2R,4S)-4-amino-1-[N-{1-(R)-(3,5-bistrifluoromethylphenyl)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-methylphenyl)piperidineas shown in Table 40 below.

Example 86

(2R,4S)-1-[N-{1-(S)-(3,5-bistrifluoromethylphenyl)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-tert-butoxycarbonylaminopiperidinewas used and treated in the same manner as in Example 85, to give(2R,4S)-4-amino-1-[N-{1-(S)-(3,5-bistrifluoromethylphenyl)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-methylphenyl)piperidineas shown in Table 40 below.

Example 87

To 2 ml of a dichloromethane solution containing 253 mg of(2R,4S)-4-amino-1-[N-{1-(R)-(3,5-bistrifluoromethylphenyl)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-methylphenyl)piperidineand 0.139 ml of triethylamine was added 0.071 ml of methanesulfonylchloride under ice-cooling, and the mixture was stirred for an hour. Thereaction mixture was poured into water and layers were separated. Theaqueous layer was extracted with chloroform, and the combined organiclayers were washed and dried, and the solvent was removed bydistillation under reduced pressure. The residue was purified by silicagel column chromatography (hexane:ethyl acetate=1:1), to give 243 mg of(2R,4S)-1-[N-{1-(R)-(3,5-bistrifluoromethylphenyl)ethyl}-N-methyl]aminocarbonyl-4-methanesulfonylamino-2-(4-fluoro-2-methylphenyl)piperidineas shown in Table 41 below.

Example 88

(2R,4S)-4-amino-1-[N-{1-(R)-(3,5-bistrifluoromethylphenyl)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-methylphenyl)piperidineand ethanesulfonyl chloride were used and treated in the same manner asin Example 87, to give(2R,4S)-1-[N-{1-(R)-(3,5-bistrifluoromethylphenyl)ethyl}-N-methyl]aminocarbonyl-4-ethanesulfonylamino-2-(4-fluoro-2-methylphenyl)piperidineas shown in Table 41 below.

Example 89

To 1 ml of a dimethylformamide solution containing 58.4 mg of(2R,4S)-1-[N-{1-(R)-(3,5-bistrifluoromethylphenyl)ethyl}-N-methyl]aminocarbonyl-4-methanesulfonylamino-2-(4-fluoro-2-methylphenyl)piperidinewas added 4.6 mg of sodium hydride under ice-cooling. The mixture wasstirred for 30 minutes and 0.010 ml of methyl iodide was added theretoand the mixture was further stirred for an hour. The reaction mixturewas poured into water, and the aqueous layer was extracted with ethylacetate. The combined organic layers were washed with water andsaturated brine and dried, and the solvent was removed by distillationunder reduced pressure. Subsequently, the residue was purified withsilica gel column chromatography (hexane:ethyl acetate=2:1), to give36.7 mg of(2R,4S)-1-[N-{1-(R)-(3,5-bistrifluoromethylphenyl)ethyl}-N-methyl]aminocarbonyl-4(N-methanesulfonyl-N-methyl)amino-2-(4-fluoro-2-methylphenyl)piperidineas shown in Table 41 below.

Example 90

(2R,4S)-1-[N-{1-(R)-(3,5-bistrifluoromethylphenyl)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-ethanesulfonylaminopiperidinewas used and treated in the same manner as in Example 89, to give(2R,4S)-1-[N-{1-(R)-(3,5-bistrifluoromethylphenyl)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-(N-methylN-ethanesulfonyl)aminopiperidine as shown in Table 41 below.

Example 91

To 20 ml of a toluene solution containing 985 mg of(2R,4S)-1-{N-(3,5-bistrifluoromethylbenzyl)-N-methyl}aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-hydroxypiperidineand 129 mg of tetrabutylammonium bromide and 10 ml of 10M aqueous sodiumhydroxide solution was added 1.21 ml of 2-(2-bromoethoxy)tetrahydropyranat room temperature, and the temperature of the mixture was raised to60° C. to 70° C. and the mixture was stirred overnight. Further addedthereto was 2.42 ml of 2-(2-bromoethoxy)tetrahydropyran and the mixturewas stirred overnight. The reaction mixture was poured into a saturatedsodium bicarbonate solution, and extracted with ethyl acetate. Theorganic layer was washed with saturated brine and dried, and the solventwas removed by distillation under reduced pressure. The residue waspurified by silica gel column chromatography (hexane:ethyl acetate=3:2),to give 1.12 g of(2R,4S)-1-{N-(3,5-bistrifluoromethylbenzyl)-N-methyl}aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-{2-(tetrahydropyran-2-yloxy)ethoxy}piperidineas shown in Table 42 below.

Example 92

To 30 ml of a methanol solution containing 1.04 g of(2R,4S)-1-{N-(3,5-bistrifluoromethylbenzyl)-N-methyl}aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-{2-(tetrahydropyran-2-yloxy)ethoxy}piperidinewas added 64 mg of p-toluenesulfonic acid monohydrate, and the mixturewas stirred for 20 minutes. The reaction mixture was concentrated underreduced pressure, and then, the residue was purified by silica gelcolumn chromatography (chloroform:ethyl acetate=1:1), give 703 mg of(2R,4S)-1-{N-(3,5-bistrifluoromethylbenzyl)-N-methyliaminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-(2-hydroxyethoxy)piperidineas shown in Table 42 below.

Example 93

To 2 ml of a tetrahydrofuran solution containing 53.6 mg of(2R,4S)-1-{N-(3,5-bistrifluoromethylbenzyl)-N-methyl}aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-(2-hydroxyethoxy)piperidine,13.8 mg of 4H-[1,2,4]-triazole and 24.4 mg of triphenylphosphine wasadded 0.092 ml of 40% diethylazodicarboxylate solution in toluene underice-cooling. The temperature of the mixture was raised to roomtemperature and the mixture was stirred overnight. Further, thetemperature was raised to 50° C., 24.4 mg of triphenylphosphine wasadded thereto, and the mixture was stirred for 30 minutes. The reactionmixture was poured into water and extracted with ethyl acetate, and theorganic layer was washed with saturated brine, dried and the solvent wasremoved by distillation. The residue was purified by silica gel columnchromatography (chloroform:ethyl acetate=1:1 andchloroform:methanol=19:1) to give 43.2 mg of(2R,4S)-1-{N-(3,5-bistrifluoromethylbenzyl)-N-methyl}aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-{2-(1,2,4)triazolylethoxy}piperidineas shown in Table 42 below.

Examples 94 and 95

The corresponding starting materials were treated in the same manner asin Example 93, to give compounds as shown in Table 42 below.

Example 96

To 2 ml of a dichloromethane solution containing 215 mg of(2R,4S)-1-{N-(3,5-bistrifluoromethylbenzyl)-N-methyl}aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-(2-hydroxyethoxy)piperidineand 0.084 ml of triethylamine was added 0.037 ml of methanesulfonylchloride under ice-cooling, and the mixture was stirred for 30 minutes.The reaction mixture was poured into water and extracted withchloroform. The organic layer was washed with brine and dried, and thesolvent was removed by distillation under reduced pressure. The residuewas purified by silica gel column chromatography (chloroform:ethylacetate=2:1), to give 189 mg of(2R,4S)-1-{N-(3,5-bistrifluoromethylbenzyl)-N-methyl}aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-(2-methanesulfonyloxyethoxy)piperidineas shown in Table 42 below.

Example 97

(1) To 1 ml of a dichloromethane solution containing 61.5 mg of(2R,4S)-1-{N-(3,5-bistrifluoromethylbenzyl)-N-methyl}aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-(2-methanesulfonyloxyethoxy)piperidine and 0.028 ml of triethylamine was added0.013 ml of morpholine under ice-cooling, and the mixture was refluxedunder heating overnight. Further added thereto was 1 ml of morpholineand the mixture was stirred for 8 hours. The reaction mixture was pouredinto water and extracted with ethyl acetate. The organic layer waswashed with saturated brine and dried, and the solvent was removed bydistillation. The residue was purified by silica gel columnchromatography (chloroform:methanol=19:1) and NH silica gel columnchromatography (hexane:ethyl acetate=2:1), to give 36.3 mg of(2R,4S)-1-{N-(3,5-bistrifluoromethylbenzyl)-N-methyl}aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-(2-morpholinoethoxy)piperidine.

(2) In 1.0 ml of chloroform was dissolved 30.7 mg of the compound of theabove (1), and 0.02 ml of 4M hydrochloric acid-ethyl acetate solutionwas added thereto. The mixture was stirred for a while and concentratedunder reduced pressure, to give 35.3 mg of(2R,4S)-1-{N-(3,5-bistrifluoromethylbenzyl)-N-methyl}aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-(2-morpholinoethoxy)piperidinehydrochloride as shown in Table 42 below.

Example 98

(2R,4S)-1-{N-(3,5-bistrifluoromethylbenzyl)-N-methyl}aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-(2-methanesulfonyloxyethoxy)piperidine and diethylamine were used and treated inthe same manner as in Example 97(1), to give(2R,4S)-1-{N-(3,5-bistrifluoromethylbenzyl)-N-methyl}aminocarbonyl-4-(2-diethylaminoethoxy)-2-(4-fluoro-2-methylphenyl)piperidineas shown in Table 42.

Example 99

In 2 ml of a dichloromethane was dissolved 200 mg of(2R,4S)-1-{N-(3,5-bistrifluoromethylbenzyl)-N-methyl}aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-hydroxypiperidine,and subsequently, 0.1 ml of ethyl isocyanate and 0.1 ml of triethylaminewere added thereto and the mixture was stirred under heating at 60° C.for 3 days. The reaction mixture was cooled down to room temperature,water and chloroform were added thereto, and layers were separated. Theaqueous layer was extracted again with chloroform, and the combinedorganic layers were dried over sodium sulfate. The solvent was removedby distillation under reduced pressure, and the residue was purified bysilica gel column chromatography (hexane:ethyl acetate=1:1), to give 78mg of(2R,4S)-1-{N-(3,5-bistrifluoromethylbenzyl)-N-methyl}aminocarbonyl-4-ethylaminocarbonyloxy-2-(4-fluoro2-methylphenyl)piperidine as shown in Table 42 below.

Example 100

In 2 ml of a dichloromethane was dissolved 200 mg of(2R,4S)-1-{N-(3,5-bistrifluoromethylbenzyl)-N-methyl}aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-hydroxypiperidine,and subsequently, 0.1 ml of morpholin-4-carboxylic chloride and 0.1 mlof triethylamine were added thereto and the mixture was stirred underheating at 60° C. for 3 days. After the reaction mixture was cooled downto room temperature, water and chloroform were added thereto, and layerswere separated: The aqueous layer was extracted again with chloroform,and the combined organic layers were dried over sodium sulfate. Afterthe solvent was removed by distillation under reduced pressure, theresidue was purified by silica gel column chromatography (hexane:ethylacetate=1:1), to give 68 mg of(2R,4S)-1-(N-(3,5-bistrifluoromethylbenzyl)-N-methyl}aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-morpholinocarbonyloxypiperidineas shown in Table 42 below.

Example 101

In 5 ml of tetrahydrofuran was dissolved 248 mg of(2R,4S)-1-{N-(3,5-bistrifluoromethylbenzyl)-N-methyl}aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-hydroxypiperidine,and subsequently, 81 mg of 1,1′-carbonyldiimidazole was added theretoand the mixture was stirred under heating at 60° C. for 16 hours. Thereaction mixture was cooled down to room temperature, water andchloroform were added and layers were separated. The aqueous layer wasextracted again with chloroform, and the combined organic layers werefurther washed with water. The organic layer was dried over sodiumsulfate, and the solvent was removed by distillation under reducedpressure. The obtained concentrated residue was purified by NH silicagel column chromatography (hexane:ethyl acetate=1:1), to give 135 mg of(2R,4S)-1-{N-(3,5-bistrifluoromethylbenzyl)-N-methyl}aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-(1-imidazolyl)carbonyloxypiperidineas shown in Table 42 below.

Example 102

(1) In 3 ml of acetonitrile was dissolved 298 mg of(2R,4S)-1-{N-(3,5-bistrifluoromethylbenzyl)-N-methyl}aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-(1-imidazolyl)carbonyloxypiperidine,and subsequently, 0.06 ml of methyl iodide was added thereto and themixture was stirred under heating for an hour. The solution was cooleddown to room temperature and the solvent was removed by distillationunder reduced pressure. To the residue were added 2.5 ml of methylenechloride, 0.11 ml of 4-methylpiperazine and 0.14 ml of triethylamine andthe mixture was stirred at room temperature for 16 hours. To thereaction mixture was added an aqueous sodium hydrogen carbonate solutionand chloroform and the mixture was stirred for 30 minutes. The layerswere separated and the obtained organic layer was washed further withwater, and dried over magnesium sulfate. The solvent was removed bydistillation under reduced pressure, and resultant residue was purifiedby NH silica gel column chromatography (hexane:ethyl acetate=2:1), togive(2R,4S)-1-{N-(3,5-bistrifluoromethylbenzyl)-N-methyl}aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-(4-methylpiperazino)carbonyloxypiperidine.

(2) The compound of the above (1) was treated with 4M hydrochloricacid-ethyl acetate solution, to give 78 mg of(2R,4S)-1-{N-(3,5-bistrifluoromethylbenzyl)-N-methyl}aminocarbonyl-4-(4-methylpiperazino)carbonyloxy-2-(4-fluoro-2-methylphenyl)piperidinehydrochloride as shown in Table 43 below.

Examples 103 to 105

The corresponding starting materials were used and treated in the samemanner as in Example 102 (1) and (2), to give the compounds as shown inTable 43 below.

Example 106

(1) In 100 ml of tetrahydrofuran were dissolved 5 g ofcis-1-{N-(3,5-bistrifluoromethylbenzyl)-N-methyl}aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-hydroxypiperidine,10.5 g of triphenylphosphine and 4.88 g of benzoic acid, andsubsequently, added thereto was 18.3 ml of a 40%diethylazodicarboxylate-toluene solution under ice-cooling and themixture was stirred at room temperature for 3 hours. To the reactionmixture were added water and ethyl acetate and the mixture was stirredfor 30 minutes. The solution was separated by layers, and the obtainedorganic layer was dried over magnesium sulfate and concentrated underreduced pressure. The residue was purified by silica gel columnchromatography (hexane:ethyl acetate=4:1), to give 4.36 g oftrans-1-{N-(3,5-bistrifluoromethylbenzyl)-N-methyl}aminocarbonyl-4-benzoyloxy-2-(4-fluoro-2-methylphenyl)piperidine.

(2) In 10 ml of methanol was dissolved 1.4 g of the compound of theabove (1), and subsequently, added thereto was 325 mg of potassiumcarbonate and the mixture was stirred at room temperature for 16 hours.After the solution was concentrated under reduced pressure for thesolvent to be removed by distillation, water and ethyl acetate wereadded thereto and layers were separated. The organic layer was driedover magnesium sulfate and concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography (hexane:ethylacetate=4:1), to give 0.68 g oftrans-1-{N-(3,5-bistrifluoromethylbenzyl)-N-methyl}aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-hydroxypiperidineas shown in Table 44 below.

Example 107

In 10 ml of tetrahydrofuran were added 98 mg oftrans-1-{N-(3,5-bistrifluoromethylbenzyl)-N-methyl}aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-hydroxypiperidine,70 mg of [1, 2,4]triazole and 262 mg of triphenylphosphine, andsubsequently added thereto was 0.48 ml of a 40%diethylazodicarboxylate-toluene solution, and the mixture was stirredunder reflux for 16 hours. After reaction is completed, an aqueoussodium bicarbonate solution and ethyl acetate were added thereto and themixture was stirred for 30 minutes. The reaction mixture was separatedby layers, and the obtained organic layer was dried over magnesiumsulfate and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (chloroform:methanol=9:1),to give 46 mg ofcis-1-{N-(3,5-bistrifluoromethylbenzyl)-N-methyl}aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-(1,2,4-triazolyl)piperidineas show in Table 44 below.

Example 108

Cis-1-{N-(3,5-bistrifluoromethylbenzyl)-N-methyl}aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-hydroxypiperidineand 4,6-dihydroxy-2-mercaptopyrimidine were used and treated in the samemanner as in Example 107, to give a compound as shown in Table 45 below.

Example 109

(2R,4S)-1-[N-{1-(R)-(3,5-bistrifluoromethylphenyl)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-hydroxypiperidinewas used and treated in the same manner as in Example 106 (1) and (2),to give(2R,4R)-1-[N-{1-(R)-(3,5-bistrifluoromethylphenyl)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-hydroxypiperidineas shown in Table 46 below.

Examples 110 to 112

The corresponding starting materials were used and treated in the samemanner as in Example 107, to give compounds as shown in Table 46 below.

Example 113

(1) 30 ml of tetrahytdrofuran solution containing 1.2 ml oftriethylphosphonoacetate was ice cooled and slowly added thereto wassodium hydride. While keeping the same temperature, the mixture wasstirred for 30 minutes and added dropwise thereto was 30 ml of atetrahydrofuran solution containing 3.02 g of(2R)-1-[N-{1-(R)-(3,5-bistrifluoromethylphenyl)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-oxopiperidine.The mixture was stirred at room temperature overnight. The reactionmixture was poured into water and extracted with ethyl acetate. Thecombined organic layers were washed with water and saturated brine anddried, and the solvent was removed by distillation under reducedpressure. The residue was purified by silica gel column chromatography(hexane:ethyl acetate=4:1), to give(2R)-1-[N-{1-(R)-(3,5-bistrifluoromethylphenyl)ethyl}-N-methyl]aminocarbonyl-4-ethoxycarbonylmethylidene-2-(4-fluoro-2-methylphenyl)piperidineas a colorless liquid.

(2) The compound of the above (1) was dissolved in 50 ml of methanol,and added thereto was 500 mg of palladium-carbon, and the mixture wasstirred under hydrogen atmosphere at room temperature overnight. Thecatalyst was removed and methanol was removed by distillation underreduced pressure, and the residue was purified by silica gel columnchromatography (hexane:ethyl acetate=4:1), to give 3.23 g of(2R)-1-[N-{1-(R)-(3,5-bistrifluoromethylphenyl)ethyl}-N-methyl]aminocarbonyl-4-ethoxycarbonylmethyl-2-(4-fluoro-2-methylphenyl)piperidineas shown in Table 46 below.

Example 114

(1) In 20 ml of methanol was dissolved 3.23 g of(2R)-1-[N-{1-(R)-(3,5-bistrifluoromethylphenyl)ethyl)-N-methyl]aminocarbonyl-4-ethoxycarbonylmethyl-2-(4-fluoro-2-methylphenyl)piperidine,and added thereto was 5.73 ml of a 2M aqueous sodium hydroxide solution.The mixture was stirred at room temperature overnight. Afterneutralizing the mixture by 2M hydrochloric acid, methanol was removedby distillation under reduced pressure, and an aqueous layer wasextracted with ethyl acetate. The organic layer was washed with waterand saturated brine and dried and the solvent was removed bydistillation under reduced pressure, to give 2.97 g of(2R)-1-[N-{1-(R)-(3,5-bistrifluoromethylphenyl)ethyl}-N-methyl]aminocarbonyl-4-carboxymethyl-2-(4-fluoro-2-methylphenyl)piperidineas yellow powder.

(2) 200 mg of the compound of the above (1) was dissolved in 2 ml ofdimethylformamide, and added thereto were 84 mg of 1-ethyl3-(3-dimethylaminopropyl)carbodiimide hydrochloride, 65 mg of1-hydroxy-1H-benzotriazole and 0.037 ml of morpholine and the mixturewas stirred at room temperature overnight. The reaction mixture wasdiluted with ethyl acetate, and washed with a saturated aqueous citricacid solution, a saturated aqueous sodium bicarbonate solution andsaturated brine. The organic layer was dried, and the solvent wasremoved by distillation to obtain the residue, and the residue waspurified by NH silica gel column chromatography (hexane:ethylacetate=2:1), to give 138 mg of(2R)-1-[N-{1-(R)-(3,5-bistrifluoromethylphenyl)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-morpholinocarbonylmethylpiperidineas shown in Table 46 below.

Examples 115 to 117

The corresponding starting materials were used and treated in the samemanner as in Example 114 (2), to give compound as shown in Table 46below.

Example 118

(1) In 10 ml of ethanol was dissolved 1.49 g of(2R)-1-[N-{1-(S)-(3,5-bistrifluoromethylphenyl)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-oxopiperidine,and added thereto was 226 mg of hydroxylamine hydrochloride, 267 mg ofsodium acetate. The mixture was stirred overnight. Ethanol was removedby distillation under reduced pressure and water was added to theresidue and extracted with ethyl acetate. The organic layer was washedwith saturated brine and dried. The solvent was removed by distillationunder reduced pressure to give a compound in a resin state.

(2) The compound of the above (1) was dissolved in 50 ml of methanol,and added thereto was 844 mg of nickel chloride. The mixture was icecooled and slowly added thereto was 224 mg of sodium borohydride. Afterstirring the mixture overnight, it was concentrated under reducedpressure, and water and ethyl acetate were added thereto and the layerswere separated. The organic layer was washed with saturated brine anddried. The solvent was removed by distillation under reduced pressure,to give 1.44 g of(2R)-4-amino-1-[N-{1-(S)-(3,5-bistrifluoromethylphenyl)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-methylphenyl)piperidineas shown in Table 47 below.

Example 119

(2R)-1-{N-(3,5-bistrifluoromethylphenyl)methylN-methyl}aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-oxopiperidine wasused and treated in the same manner as in Example 119 (1) and (2), togive(2R)-4-amino-1-{N-(3,5-bistrifluoromethylphenyl)methyl-N-methyl}aminocarbonyl-2-(4-fluoro-2-methylphenyl)piperidineas shown in Table47 below.

Example 120

(2R)-4-amino-1-[N-{1-(S)-(3,5-bistrifluoromethylphenyl)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-methylphenyl)piperidinewas used and treated in the same manner as in Example 50, to give (a)(2R,4S)-1-[N-{1-(S)-(3,5-bistrifluoromethylphenyl)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-(2-pyrazinylcarbonylamino)piperidineand (b)(2R,4R)-1-[N-{1-(S)-(3,5-bistrifluoromethylphenyl)ethyl)-N-methyl]aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-(2-pyrazinylcarbonylamino)piperidineas shown in Table 47 below.

Example 121

In 2 ml of an acetonitrile solution containing 80 mg of(2R,4S)-1-(N-{1-(S)-(3,5-bistrifluoromethylphenyl)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-morpholinopiperidinewas added 0.034 ml of methyl iodide and the mixture was stirred at 60°C. overnight. The solvent was removed by distillation, and precipitatedyellow powder was dried, to give 98 mg of(2R,4S)-1-[N-{1-(S)-(3,5-bistrifluoromethylphenyl)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-(N-methyl-4-morpholinio)piperidineiodide as shown in Table 48 below.

Example 122

(2R,4S)-1-(N-(1-(R)-(3,5-bistrifluoromethylphenyl)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-morpholinopiperidinewas used and treated in the same manner as in Example 121, togive(2R,4S)-1-[N-{1-(R)-(3,5-bistrifluoromethylphenyl)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-(N-methyl-4-morpholinio)piperidineiodide as show in Table 48 below.

Example 123

In 2 ml of a dichloromethane solution containing 80 mg of(2R,4S)-1-[N-{1-(S)-(3,5-bistrifluoromethylphenyl)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-morpholinopiperidinewas added 34 mg of 3-chloroperbenzoic acid, and the mixture was stirredat room temperature overnight. The reaction mixture was poured into asaturated aqueous sodium bicarbonate solution, and the aqueous layer wasextracted with dichloromethane. The combined organic layers were washedwith water and saturated brine and dried, and the solvent was removed bydistillation under reduced pressure. The precipitated white powder wasdried, to give 79 mg of(2R,4S)-1-[N-{1-(S)-(3,5-bistrifluoromethylphenyl)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-(N-oxomorpholino)piperidine as shown in Table 48 below.

Example 124

(2R,4S)-1-[N-{1-(R)-(3,5-bistrifluoromethylphenyl)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-morpholinopiperidinewas used and treated in the same manner as in Example 123, to give(2R,4S)-1-[N-{1-(R)-(3,5-bistrifluoromethylphenyl)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-(N-oxomorpholino)piperidine as shown in Table 48 below.

Examples 125 to 127

The corresponding starting materials were used and treated in the samemanner as in Example 8, to give compounds as shown in Table 49 below.

Examples 128 to 136

The corresponding starting materials were used and treated in the samemanner as in Example 50, to give compounds as shown in Tables 49 to 51below.

Example 137

In 2 ml of dichloromethane was dissolved 263 mg of(2R)-4-amino-1-[N-(3,5-bistrifluoromethylbenzyl)-N-methyl]aminocarbonyl-2-(4-fluoro-2-methylphenyl)piperidine,and at room temperature, were added thereto 52 μl of 2-chloroethylisocyanate and 167 μl of triethylamine, and the mixture was stirredfor 2 hours. To the solution was added a saturated sodium hydrogencarbonate solution, the dichloromethane layer was separated, and theaqueous layer was further extracted with chloroform. The combinedorganic layers were washed with saturated brine, dried and concentrated.The residue was purified by silica gel column chromatography(chloroform:methanol=9:1), to give 109 mg of(2R)-4-(2-chloroethyl)ureido-1-[N-(3,5-bistrifluoromethylbenzyl)-N-methyl]aminocarbonyl-2-(4-fluoro-2-methylphenyl)piperidineas shown in Table 51.

Example 138

In 20 ml of dimethylformamide were dissolved 2.65 g of(2R)-4-amino-1-[N-(3,5-bistrifluoromethylbenzyl)-N-methyl]aminocarbonyl-2-(4-fluoro-2-methylphenyl)piperidinehydrochloride and 1 g of 5-formylfuran-2-carboxylic acid, and addedthereto were 1.92 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride, 0.6 g of 1-hydroxy-1H-benzotriazole and 1.4 ml oftriethylamine. The mixture was stirred at room temperature for 3 hours.After the reaction was completed, an aqueous citric acid solution andethyl acetate were added thereto and layers were separated. The organiclayer was further washed with saturated brine, and the combined organiclayers were dried over magnesium sulfate, and concentrated under reducedpressure. The residue was purified by NH silica gel columnchromatography (hexane:ethyl acetate=2:1), to give 289 mg of (a)(2R,4S)-1-[N-(3,5-bistrifluoromethylbenzyl)-N-methyl]aminocarbonyl-4-(5-formylfuran-2-yl)carbamoyl-2-(4-fluoro-2-methylphenyl)piperidineand 185 mg of (b)(2R,4S)-1-[N-(3,5-bistrifluoromethylbenzyl)-N-methyl]aminocarbonyl-4-(5-formylfuran-2-yl)carbamoyl-2-(4-fluoro-2-methylphenyl)piperidineas shown in Table 52 below.

Examples 140 to 168

The corresponding starting materials were used and treated in the samemanner as in Example 138, to give compounds as shown in Tables 53 to 57below.

Example 169

In 1 ml of tetrahydrofuran was dissolved 80 mg of(2R,4S)-4-amino-1-[N-{1-(S)-(3,5-bistrifluoromethylphenyl)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-methylphenyl)piperidine,and under ice-cooling, 25.7 mg of 1,1-carbonyldiimidazole was addedthereto and the mixture was stirred under ice-cooling for 30 minutes. Tothe solution, 19 μl of 2-aminoethanol, 44 μl of triethylamine were addedunder ice-cooling, and the mixture was stirred at room temperature for22 hours. The solvent was removed by distillation and to the residue,and added thereto were water and dichloromethane and layers wereseparated. The organic layer was washed with saturated brine, dried andconcentrated. To the residue was added isopropyl ether, and precipitatedwhite crystals were collected by filtration, to give 74 mg of(2R,4S)-1-[N-{1-(S)-(3,5-bistrifluoromethylphenyl)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-(2-hydroxyethyl)ureidopiperidineas shown in Table 57 below.

Examples 170 to 173

The corresponding starting materials were used and treated in the samemanner as in Example 169, to give compounds as shown in Table 57 below.

Examples 174 to 177

The corresponding starting materials were used and treated in the samemanner as in Example 87, to give compounds as shown in Table 58 below.

Example 178

In 10 ml of dichloromethane was dissolved 1.01 g of(2R,4S)-4-amino-1-[N-{1-(R)-(3,5-bistrifluoromethylphenyl)ethyl{-N-methyl]aminocarbonyl-2-(4-fluoro-2-methylphenyl)piperidineand 0.558 ml of triethylamine, and under ice-cooling, added thereto was0.314 ml of 2-chloroethanesulfonylchloride, and the mixture was stirredfor 4 hours. The solution was poured into water, layers were separated,and the aqueous layer was further extracted with dichloromethane. Thecombined organic layers were washed with saturated brine, dried andconcentrated. The residue was purified by silica gel columnchromatography (hexane:ethyl acetate=2:1), to give 725 mg of(2R,4S)-1-[N-{1-(R)-(3,5-bistrifluoromethylphenyl)ethyl}-N-methyl]aminocarbonyl-4-ethylenesulfonylamino-2-(4-fluoro-2-methylphenyl)piperidineas shown in Table 58 below.

Example 179

(2R,4S)-1-[N-{1-(R)-(3,5-bistrifluoromethylphenyl)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-methylaminopiperidinewas used and treated in the same manner as in Example 178, to give(2R,4S)-1-[N-{1-(R)-(3,5-bistrifluoromethylphenyl)ethyl}-N-methyl]aminocarbonyl-4-(1-ethylenesulfonyl-1-methylamino)-2-(4-fluoro-2-methylphenyl)piperidineas shown in Table 58.

Examples 180 to 181

The corresponding starting materials were used and treated in the samemanner as in Example 87, to give compounds as shown in Table 59 below.

Examples 183 to 184

The corresponding starting materials were used and treated in the samemanner as in Example 89, to give compounds as shown in Table 59 below.

Example 185

(2R,4S)-1-[N-{1-(S)-(3,5-bistrifluoromethylphenyl)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-hydroxypiperidineand 2-methoxyethyl chloride were used and treated in the same manner asin Example 91, to give(2R,4S)-1-[N-{1-(S)-(3,5-bistrifluoromethylphenyl)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-(2-methoxyethoxy)piperidineas shown in Table 59 below.

Examples 186 to 189

The corresponding starting materials were used and treated in the samemanner as in Example 91 and Example 92, to give compounds as shown inTables 59 to 60 below.

Example 190

(2R,4S)-1-[N-{1-(R)-(3,5-bistrifluoromethylphenyl)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-(2-hydroxyethoxy)piperidineand methanesulfonyl chloride were used and treated in the same manner asin Example 96, to give(2R,4S)-1-[N-{1-(R)-(3,5-bistrifluoromethylphenyl)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-(2-methanesulfonyloxyethoxy)-piperidineas shown in Table 60 below.

Examples 191 to 196

The corresponding starting materials were used and treated in the samemanner as in Example 97, to give compounds as shown in Tables 60 to 61below.

Examples 197 to 198

The corresponding starting materials were used and treated in the samemanner as in Example 101, to give compounds as shown in Table 62 below.

Examples 199 to 205

The corresponding starting materials were used and treated in the samemanner as in Example 102 (1) or in Example 102 (1) and (2), to givecompounds as shown in Table 63 below.

Example 206

(2R,4S)-1-[N-(3,5-bistrifluoromethylbenzyl)-N-methyl]aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-piperidinopiperidinewere used and treated in the same manner as in Example 123, to give(2R,4S)-1-[N-(3,5-bistrifluoromethylbenzyl)-N-methyl]aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-(N-oxopiperidino)piperidineas shown in Table 65 below.

Example 207

In 4 ml of ethanol was dissolved 124 mg of(2R,4S)-1-[N-(3,5-bistrifluoromethylbenzyl)-N-methyl]aminocarbonyl-4-(5-formylfuran-2-yl)carbamoyl-2-(4-fluoro-2-methylphenyl)piperidine,and added thereto was 3.8 mg of sodium borohydride, and the mixture wasstirred at room temperature for 2 hours. To the solution was added anaqueous sodium hydrogen carbonate solution, and the mixture was stirredfor 10 minutes and concentrated, and ethanol was removed bydistillation. To the residue was added ethyl acetate and water, andlayers were separated. The organic layer was dried and concentrated. Theresidue was purified by silica gel column chromatography(chloroform:methanol=19:1), to give 68 mg of(2R,4S)-1-[N-(3,5-bistrifluoromethylbenzyl)-N-methyl]aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-(5-hydroxymethylfuran-2-yl)carbamoylpiperidineas shown in Table 65 below.

Example 208

In 4 ml of dichloroethane were dissolved 124 mg of(2R,4S)-1-[N-(3,5-bistrifluoromethylbenzyl)-N-methyl]aminocarbonyl-4-(5-formylfuran-2-yl)carbamoyl-2-(4-fluoro-2-methylphenyl)piperidine,44 μl of morpholine and 2.9 μl of acetic acid, and added thereto 106 mgof sodium triacetoxyborohydride, and the mixture was stirred at roomtemperature for 3 hours. To the solution was added an aqueous sodiumcarbonate solution and chloroform, and the mixture was stirred for 10minutes and layers were separated. The organic layer was dried overmagnesium sulfate and concentrated. The residue was purified by NHsilica gel column chromatography (n-hexane:ethyl acetate=l:1). Theobtained oily substance was treated with 4M hydrochloric acid-ethylacetate solution, to give 78 mg of(2R,4S)-1-[N-(3,5-bistrifluoromethylbenzyl)-N-methyl]aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-(5-morpholinomethylfuran-2-yl)carbamoylpiperidinehydrochloride as shown in Table 65 below.

Example 209

In mixture of 3.3 ml of toluene and 0.4 ml of dichloromethane wasdissolved 197 mg of(2R,4S)-1-[N-(3,5-bistrifluoromethylbenzyl)-N-methyl]aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-hydroxypiperidine,and added thereto was 78 mg of 1,1′-carbonyldiimidazole. The mixture wasstirred at 60° C. for 4 hours. Distilled water was added thereto and themixture was extracted with chloroform, dried over magnesium sulfate andconcentrated under reduced pressure. The residue was dissolved in 3.7 mlof acetonitrile, and added thereto was 100 μl of methyl iodide, and themixture was stirred at 50° C. for 3 hours. The solution was concentratedunder reduced pressure, and to the residue were added 3.6 ml of tolueneand 156 μl of thiomorpholine, and the mixture was stirred at 70° C. for16 hours. Distilled water was added thereto and the mixture wasextracted with chloroform, dried over magnesium sulfate and concentratedunder reduced pressure. The residue was purified by silica gel columnchromatography (hexane: ethyl acetate=2:1→1:2), to give 197 mg of(2R,4S)-1-[N-(3,5-bistrifluoromethylbenzyl)-N-methyl)aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-thiomorpholinocarbonyloxypiperidineas shown in Table 65 below.

Examples 210 to 212

The corresponding starting materials were used and treated in the samemanner as in Example 209, to give compounds as shown in Table 65 below.

Example 213

In 1.9 ml of dichloromethane was dissolved 62 mg of(2R,4S)-1-[N-(3,5-bistrifluoromethylbenzyl)-N-methyl]aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-thiomorpholinocarbonyloxypiperidine,and under ice-cooling, 22 mg of 3-chloroperbenzoic acid was addedthereto and the mixture was stirred at 0° C. for 30 minutes. Thesolution was extracted by adding a 0.1M aqueous sodium hydroxidesolution and ethyl acetate. The organic layer was dried over magnesiumsulfate and concentrated. The residue was purified by thin-layer silicagel chromatography (chloroform:acetone=4:1), to give 63 mg of(2R,4S)-1-[N-(3,5-bistrifluoromethylbenzyl)-N-methyl]aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-(1-oxothiomorpholino)carbonyloxypiperidineas shown in Table 65 below.

Example 214

In 2.4 ml of dichloromethane was dissolved 79 mg of(2R,4S)-1-[N-(3,5-bistrifluoromethylbenzyl)-N-methyl]aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-thiomorpholinocarbonyloxypiperidine,and added thereto was 68 mg of 3-chloroperbenzoic acid, and the mixturewas stirred at room temperature for 4 hours. The solution was extractedby adding a 01.M aqueous sodium hydroxide solution and ethyl acetate.The organic layer was dried over magnesium sulfate and concentrated. Theresidue was purified by thin-layer silica gel chromatography(chloroform:acetone=4:1), to give 76 mg of(2R,4S)-1-(N-(3,5-bistrifluoromethylbenzyl)-N-methyl]aminocarbonyl-4-(1,1-dioxothiomorpholino)carbonyloxy-2-(4-fluoro-2-methylphenyl)piperidineas shown in Table 65 below.

Example 215

In 1 ml of tetrahydrofuran was dissolved 78 mg of(2R,4S)-1-[N-{1-(R)-(3,5-bistrifluoromethylphenyl)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-(2,2,5-trimethyl[1,3]dioxolan-5-yl)carbamoylpiperidine,and under ice-cooling, 0.5 ml of a 2M aqueous hydrochloric acid solutionwas added thereto. After 15 minutes, the temperature was raised to roomtemperature and the mixture was further stirred for 30 minutes. Themixture was poured into a saturated aqueous sodium hydrogen carbonatesolution, and extracted with ethyl acetate. The organic layer was washedwith saturated brine, dried and concentrated. The residue was purifiedby silica gel column chromatography (chloroform:ethyl acetate=2:1), togive 64 mg of(2R,4S)-1-[N-{1-(R)-(3,5-bistrifluoromethylphenyl)ethyl]-N-methyl]aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-{1,1-di(hydroxymethyl)ethyl}carbamoylpiperidineas shown in Table 66 below.

Example 216

In 1 ml of dichloromethane was dissolved 50.5 mg of(2R,4S)-4-amino-1-[N-{1-(R)-(3,5-bistrifluoromethylphenyl)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-methylphenyl)piperidine,and under ice-cooling, 25.3 mg of methylisocyanate was added thereto.After the temperature of the mixture was raised to room temperature, themixture was stirred for 30 minutes. The solution was poured into water,the dichloromethane layer was separated and the aqueous layer wasfurther extracted with chloroform. The combined organic layers werewashed with saturated brine, dried and concentrated. The residue waspurified by silica gel column chromatography (chloroform:methanol=19:1),to give 47.9 mg of(2R,4S)-1-[N-{1-(R)-(3,5-bistrifluoromethylphenyl)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-methylureidopiperidineas shown in Table 66 below.

Example 217

(2R,4S)-4-amino-1-[N-(1-(R)-(3,5-bistrifluoromethylphenyl)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-methylphenyl)piperidineand tert-butyl isocyanate were used and treated in the same manner as inExample 216, to give(2R,4S)-1-[N-{1-(R)-(3,5-bistrifluoromethylphenyl)ethyl}-N-methyl]aminocarbonyl-4-tert-butylureido-2-(4-fluoro-2-methylphenyl)piperidineas shown in Table 66.

Example 218

In 1 ml of dichloromethane was dissolved 50.5 mg of(2R,4S)-4-amino-1-[N-{1-(R)-(3,5-bistrifluoromethylphenyl)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-methylphenyl)piperidine,and under ice-cooling, 42 μl of triethylamine and 18 μl ofdimethylcarbamoyl chloride were added thereto. After the temperature ofthe mixture was raised to room temperature, the mixture was stirredovernight. The solvent was poured into water, and the dichloromethanelayer was separated, and the aqueous layer was further extracted withchloroform. The combined organic layers were washed with saturatedbrine, dried and concentrated. The residue was purified by silica gelcolumn chromatography (chloroform:methanol=39:1), to give 41.8 mg of(2R,4S)-1-[N-{1-(R)-(3,5-bistrifluoromethylphenyl)ethyl}-N-methyl]aminocarbonyl-4-(3,3-dimethylureido)-2-(4-fluoro-2-methylphenyl)piperidineas shown in Table 66 below.

Examples 219 to 224

The corresponding starting materials were used and treated in the samemanner as in Example 216, to give compounds as shown in Table 67 below.

Example 225

(1) 80 mg of(2R,4S)-4-amino-1-[N-{1-(S)-(3,5-bistrifluoromethylphenyl)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-methylphenyl)piperidinewas used and treated in the same manner as in Example 216, to give(2R,4S)-1-[N-{1-(S)-(3,5-bistrifluoromethylphenyl)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-(4-methylpiperazinocarbamoyl)piperidine.

(2) The compound of the above (1) was dissolved in 1 ml of ethylacetate, and under ice-cooling, 0.5 ml of 4M hydrochloric acid-ethylacetate solution was added thereto and the mixture was stirred for 30minutes under ice-cooling. The solvent was removed by distillation underreduced pressure and added thereto was diethyl ether. Precipitated whitecrystals were collected by filtration, to give 80 mg of(2R,4S)-1-[N-{1-(S)-(3,5-bistrifluoromethylphenyl)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-(4-methylpiperazinocarbamoyl)piperidinehydrochloride as shown in Table 67 below.

Example 226

In 2 ml of dichloromethane was dissolved 100 mg of(2R,4S)-4-amino-1-[N-{1-(S)-(3,5-bistrifluoromethylphenyl)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-methylphenyl)piperidine,and under ice-cooling, 33 μl of triethylamine and 19 μl ofmethylchloroformate were added thereto and the mixture was stirred underice-cooling for 30 minutes. The solution was poured into water and thedichloromethane layer was separated, and the aqueous layer was furtherextracted with dichloromethane. The combined organic layers were washedwith saturated brine, dried and concentrated. The residue was purifiedby silica gel column chromatography (chloroform:methanol=19:1), to give80 mg of(2R,4S)-1-[N-{1-(S)-(3,5-bistrifluoromethylphenyl)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-methoxycarbamoylpiperidineas shown in Table 66 below.

Examples 227 to 229

The corresponding starting materials were used and treated in the samemanner as in Example 226, to give compounds as shown in Table 68 below.

Example 230

In 1.2 ml of acetonitrile was dissolved 22 mg of 2-ethoxy-ethanol, and94 mg of N,N′-disuccinimidylcarbonate and 0.1 ml of triethylamine wereadded thereto, and the mixture was stirred at room temperature for 1.5hours. The solvent was removed by distillation, and to the residue wereadded a saturated aqueous sodium hydrogen carbonate solution and ethylacetate, and extracted. The organic layer was washed with saturatedbrine, dried, and concentrated. The residue was dissolved in 0.8 ml ofdichloromethane, and added thereto were 80 mg of(2R,4S)-4-amino-1-[N-{1-(S)-(3,5-bistrifluoromethylphenyl)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-methylphenyl)piperidineand 33 μl of triethylamine, and the mixture was stirred at roomtemperature for 30 minutes. To the solution were added a saturatedaqueous sodium hydrogen carbonate solution and dichloromethane andextracted. The combined organic layers were washed with saturated brine,dried and concentrated. The residue was purified by thin-layer silicagel chromatography (chloroform:methanol=19:1), to give 85 mg of(2R,4S)-1-[N-{1-(S)-(3,5-bistrifluoromethylphenyl)ethyl}-N-methyl]aminocarbonyl-4-(2-ethoxyethoxy)carbamoyl-2-(4-fluoro-2-methylphenyl)piperidineas shown in Table 68 below.

Example 231

3-hydroxy-3-methylbutanol and(2R,4S)-4-amino-1-[N-{1-(S)-(3,5-bistrifluoromethylphenyl)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-methylphenyl)piperidinewere used and treated in the same manner as in Example 230, to give(2R,4S)-1-[N-{1-(S)-(3,5-bistrifluoromethylphenyl)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-(3-hydroxy-3-methylbutoxy)carbamoylpiperidineas shown in Table 68 below.

Example 232

(1) In 1 ml of tetrahydrofuran was dissolved 119 mg of(2R,4S)-1-[N-{1-(R)-(3,5-bistrifluoromethylphenyl)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-vinylsulfonylaminopiperidine.Added thereto was 26 μl of morpholine at room temperature, and themixture was refluxed under heating. Five hours later, 26 μl ofmorpholine was added and the mixture was further refluxed under heatingfor 2.5 hours. The solution was concentrated and the residue waspurified by silica gel column chromatography (chloroform:methanol=19:1),to give 129 mg of(2R,4S)-1-[N-{1-(R)-(3,5-bistrifluoromethylphenyl)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-(2-morpholinoethyl)sulfonylaminopiperidine.

(2) In 1 ml of chloroform was dissolved 34.1 mg of the compound of theabove (1), and added thereto 25 μl of 4M hydrochloric acid-ethyl acetatesolution. The mixture was concentrated, to give 33.1 mg of(2R,4S)-1-[N-{1-(R)-(3,5-bistrifluoromethylphenyl)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-(2-morpholinoethyl)sulfonylaminopiperidinehydrochloride as shown in Table 69 below.

Examples 233 to 238

The corresponding starting materials were used and treated in the samemanner as in Example 232 (1) and (2), to give compounds as shown inTable 69 below.

Example 239

In mixture of 1.6 ml of dimethylformamide and 0.2 ml of dichloromethanewas dissolved 101 mg of(2R,4S)-1-[N-{1-(S)-(3,5-bistrifluoromethylphenyl)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-hydroxypiperidine,and added thereto were 39 mg of (S)-(−)-2-pyrrolidone-5-carboxilic acid,58 mg of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and12 mg of 4-(dimethylamino)pyridine, and the mixture was stirred at roomtemperature for 6 hours, followed by stirring at 60° C. for 4 days. Tothe solution was added a 5% aqueous citric acid solution, and themixture was extracted with chloroform. The organic layer was washed witha saturated aqueous sodium hydrogen carbonate solution and saturatedbrine, and dried over magnesium sulfate and concentrated. The residuewas purified by silica gel column chromatography(chloroform:acetone=4:1→2:1), to give 64 mg of(2R,4S)-1-[N-{1-(S)-(3,5-bistrifluoromethylphenyl)ethyl}-N-methyl]aminocarbonyl-4-((2S)-5-oxopyrrolidin-2-yl}carbonyloxy-2-(4-fluoro-2-methylphenyl)piperidineas shown in Table 70 below.

Example 240

(1) In a mixture of 3.2 ml of toluene and 0.4 ml of dichloromethane wasdissolved 179 mg of(2R,4S)-1-[N-{1-(S)-(3,5-bistrifluoromethylphenyl)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-hydroxypiperidine,and added thereto was 69 mg of 1,1′-carbonyldiimidazole, and the mixturewas stirred at 60° C. for 3 hours. Distilled water was added thereto andthe mixture was extracted with chloroform. The organic layer was driedover magnesium sulfate, and concentrated under reduced pressure. Theresidue was dissolved in 3.2 ml of acetonitrile, 88 μl of methyl iodidewas added thereto, and the mixture was stirred at 50° C. for 3 hours.After the solution was concentrated, 3.2 ml of toluene and 114 μl ofthiazolidine were added and the mixture was stirred at 70° C. for 16hours. Distilled water was added thereto and the mixture was extractedwith chloroform. The organic layer was dried over magnesium sulfate andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (hexane:ethyl acetate=:1:1→1:2), to give 141mg of(2R,4S)-1-[N-{1-(S)-(3,5-bistrifluoromethylphenyl)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-(1,3-tetrahydrothiazol-3-yl)carbonyloxypiperidine.

(2) In 2 ml of dichloroethane was dissolved 62 mg of the compound of theabove (1), and under ice-cooling, 22 mg of 3-chloroperbenzoic acid wasadded thereto and the mixture was stirred at 0° C. for an hour. To themixture was added a saturated aqueous sodium hydrogen carbonate solutionand extracted. The organic layer was dried over magnesium sulfate andconcentrated under reduced pressure. The residue was purified bythin-layer silica gel chromatography (chloroform:acetone=4:1), to give42 mg of(2R,4S)-1-[N-{1-(S)-(3,5-bistrifluoromethylphenyl)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-(1-oxo-1,3-tetrahydrothiazol-3-yl)carbonyloxypiperidineas shown in Table 70 below.

Example 241

(1) In 1.9 ml of toluene was dissolved 101 mg of(2R,4S)-1-[N-{1-(S)-(3,5-bistrifluoromethylphenyl)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-hydroxypiperidine,and added thereto were 46 μl of isocyanate acetic acid ethyl ester andone drop of acetic acid, and the mixture was stirred at 70° C. for 16hours. The solution was concentrated and the residue was purified bysilica gel column chromatography (hexane:ethyl acetate=2:1→1:1), to give124 mg of(2R,4S)-1-[N-{1-(S)-(3,5-bistrifluoromethylphenyl)ethyl}-N-methyl]aminocarbonyl-4-ethoxycarbonylmethylaminocarbonyloxy-2-(4-fluoro-2-methylphenyl)piperidine.

(2) In a mixture of 1.35 ml of tetrahydrofuran and 0.15 ml of methanolwas dissolved 106 mg of the compound of the above (1), and added theretowas 92 μl of a 2M aqueous sodium hydroxide solution, and the mixture wasstirred at room temperature for 1 hour. After the solution wasconcentrated, a 10% aqueous citric acid solution was added thereto, andthe precipitates were collected by filtration and washed with water, togive 92 mg of(2R,4S)-1-[N-{1-(S)-(3,5-bistrifluoromethylphenyl)ethyl}-N-methyl]aminocarbonyl-4-carboxymethylaminocarbonyloxy-2-(4-fluoro-2-methylphenyl)piperidineas shown in Table 70 below.

Example 242

In 0.9 ml of dimethylformamide was dissolved 61 mg of(2R,4S)-1-[N-{1-(S)-(3,5-bistrifluoromethylphenyl)ethyl}-N-methyl]aminocarbonyl-4-carboxymethylaminocarbonyloxy-2-(4-fluoro-2-methylphenyl)piperidine,and added thereto were 9 μl of morpholine, 15 mg of1-hydroxybenzotriazole monohydrate and 19 mg of1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, and themixture was stirred at room temperature for a day. To the solution wasadded distilled water and the mixture was extracted with chloroform, andthe organic layer was dried over magnesium sulfate and concentrated. Theresidue was purified by silica gel column chromatography(chloroform:methanol=19:1), to give 50 mg of(2R,4S)-1-[N-{1-(S)-(3,5-bistrifluoromethylphenyl)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-morpholinocarbonylmethylaminocarbonyloxypiperidineas shown in Table 70 below.

Example 243

In 1.9 ml of toluene was dissolved 101 mg of(2R,4S)-1-[N-{1-(S)-(3,5-bistrifluoromethylphenyl)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-hydroxypiperidine,and added thereto was 37 μl of chlorosulfonylisocyanate, and the mixturewas stirred at room temperature for 10 minutes. Added thereto was 207 μlof diethylamine, and the mixture was stirred at room temperature for anhour. To the solution was added distilled water, and the mixture wasextracted with chloroform. The organic layer was dried over magnesiumsulfate and concentrated. The residue was purified by silica gel columnchromatography (chloroform:methanol=19:1), to give 116 mg of(2R,4S)-1-[N-{1-(S)-(3,5-bistrifluoromethylphenyl)ethyl}-N-methyl]aminocarbonyl-4-diethylaminosulfonylaminocarbonyloxy-2-(4-fluoro-2-methylphenyl)piperidineas shown in Table 70 below.

Example 244

(2R,4S)-1-[N-(3,5-bistrifluoromethylbenzyl)-N-methyl]aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-hydroxypiperidineand (S)-(−)-2-pyrrolidone-5-carboxylic acid were used and treated in thesame manner as in Example 239, to give(2R,4S)-1-[N-(3,5-bistrifluoromethylbenzyl)-N-methyl]aminocarbonyl-4-[(2S)-5-oxopyrrolidin-2-yl}carbonyloxy-2-(4-fluoro-2-methylphenyl)piperidineas shown in Table 70 below.

Example 245

In 2 ml of toluene were dissolved 264 mg of(2R)-4-amino-1-[N-(3,5-bistrifluoromethylbenzyl)-N-methyl]aminocarbonyl-2-(4-fluoro-2-methylphenyl)piperidinehydrochloride, 80 mg of 2-bromopyridine, 12 mg of palladium acetate, 32mg of 2,2′-bis(diphenylphosphino)-1,1′-bisnaphtyl and 48 mg of sodiumtert-butoxide, and the mixture was stirred at 80° C. for 16 hours. Thesolution was cooled down to room temperature, and added thereto wereethyl acetate and an aqueous sodium hydrogen carbonate solution and themixture was extracted. The organic layer was dried over magnesiumsulfate and concentrated. The residue was purified by NH silica gelcolumn chromatography (hexane:ethyl acetate=2:1), to give 68 mg of (a)(2R,4S)-1-[N-(3,5-bistrifluoromethylbenzyl)-N-methyl]aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-(2-pyridylamino)piperidineand 56 mg of (b)(2R,4R)-1-[N-(3,5-bistrifluoromethylbenzyl)-N-methyl]aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-(2-pyridylamino)piperidineas shown in Table 71 below.

Examples 246 to 247

The corresponding starting materials were used and treated in the samemanner as in Example 245, to give compounds as shown in Tables 71 to 72below.

Examples 248 to 249

The corresponding starting materials were used and treated in the samemanner as in Example 75, to give compounds as shown in Table 72 below.

Example 250

(1) In 5 ml of tetrahydrofuran was dissolved 800 mg of(2R,4S)-1-[N-{1-(S)-(3,5-bistrifluoromethylphenyl)ethyl}-N-methyl]aminocarbonyl-4-ethoxycarbonyl-2-(4-fluoro-2-methylphenyl)piperidine,and 5 ml of a 2M aqueous sodium hydroxide solution was added thereto andthe mixture was stirred at room temperature for 3 days. To the reactionmixture was added an aqueous citric acid solution to make it acidic, andthe mixture was extracted with ethyl acetate. The organic layer waswashed with saturated brine and dried. This solution was concentrated,to give 700 mg of(2R,4S)-1-[N-{1-(S)-(3,5-bistrifluoromethylphenyl)ethyl}-N-methyl]aminocarbonyl-4-carboxy-2-(4-fluoro-2-methylphenyl)piperidine.

(2) In dimethylformamide was dissolved 110 mg of the compound of theabove (1), and added thereto were 96 mg of1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride, 30 mg of1-hydroxybenzotriazole, 0.1 ml of a 40% aqueous ammonium solution, andthe mixture was stirred at room temperature for 3 hours. To the solutionwere added an aqueous citric acid solution and ethyl acetate, and thelayers were separated. The organic layer was washed with saturatedbrine, dried and concentrated. The residue was purified by silica gelcolumn chromatography (chloroform:methanol=9:1), to give 87 mg of(2R,4S)-4-aminocarbonyl-1-[N-{1-(S)-(3,5-bistrifluoromethylphenyl)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-methylphenyl)piperidineas shown in Table 73 below.

Examples 251 to 253

The corresponding starting materials were used and treated in the samemanner as in Example 250 (1) and (2) or Example 250 (2), to givecompounds as shown in Table 73 below.

Example 254

(1) In 40 ml of tetrahydrofuran was dissolved 2 g of(2R,4S)-1-[N-{1-(R)-(3,5-bistrifluoromethylphenyl)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-hydroxypiperidine,and added thereto were 1.59 g of carbon tetrabromide and 1.26 g oftriphenylphosphine, and the mixture was stirred at room temperature for2 hours. To the solution was added 80 ml of diethyl ether, and afterstirring the mixture, precipitated insoluble matters were removed byfiltration. The organic layer was concentrated and the residue waspurified by silica gel column chromatography (n-hexane:ethylacetate=10:1), to give 1.26 g of(2R,4R)-1-[N-{1-(S)-(3,5-bistrifluoromethylphenyl)ethyl}-N-methyl]aminocarbonyl-4-bromo-2-(4-fluoro-2-methylphenyl)piperidine.

(2) In 20 ml of dimethylformamide was dissolved 1.14 g of the compoundof the above (1), and added thereto was 1.14 g of potassium thioacetateand the mixture was stirred at 80° C. for 2 hours. After the solutionwas cooled down to room temperature, an aqueous citric acid solution andethyl acetate were added thereto and layers were separated. The organiclayer was washed with saturated brine, dried and concentrated. Theresidue was purified by silica gel column chromatography (n-hexane:ethylacetate=6:1), to give 920 mg of(2R,4S)-4-acetylthio-1-[N-{1-(S)-(3,5-bistrifluoromethylphenyl)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-methylphenyl)piperidineas shown in Table 74 below.

Examples 255 to 256

The corresponding starting materials were used and treated in the samemanner as in Example 254 (1) and (2), to give compounds as shown inTable 74 below.

Example 257

In 10 ml of methanol was dissolved 880 mg of(2R,4S)-4-acetylthio-1-[N-{1-(S)-(3,5-bistrifluoromethylphenyl)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-methylphenyl)piperidine,and added thereto were methyl iodide and 5 ml of a 1M aqueous sodiumhydroxide solution, and the mixture was stirred at room temperature for2 hours. To the solution was added an aqueous citric acid solution toneutralize the same, and methanol was removed by distillation. To theresidue were added ethyl acetate and saturated brine and layers wereseparated. The organic layer was dried and concentrated. The residue waspurified by silica gel column chromatography ( n-hexane:ethylacetate=6:1), to give 560 mg of(2R,4S)-1-[N-{1-(S)-(3,5-bistrifluoromethylphenyl)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-methylthiopiperidineas shown in Table 74 below.

Examples 258 to 263

The corresponding starting materials were used and treated in the samemanner as in Example 257, to give compounds as shown in Tables 74 to 75below.

Examples 264 to 270

The corresponding starting materials were used and treated in the samemanner as in Example 213, to give compounds as shown in Tables 76 to 77below.

Examples 271 to 278

The corresponding starting materials were used and treated in the samemanner as in Example 214, to give compounds as shown in Tables 78 to 79below.

Examples 279 to 312

The corresponding starting materials were used and treated in the samemanner as in Example 138, to give compounds as shown in Tables 80 to 87below.

Example 313

To 4.2 ml of 4M hydrochloric acid in ethyl acetate was added 361 mg of(2R,4S)-1-{N-(3,5-bistrifluoromethylbenzyl)-N-methyl}amino-carbonyl-4-[{(2S,4R)-4-benzyloxy-1-tert-butyloxycarbonyl-pyrrolidin-2-ylcarbonyl}amino]-2-(4-fluoro-2-methylphenyl)-piperidineand the mixture was stirred for 1 hour at room temperature. After theevaporation in vacuo the residue was triturated with hexane and thesolvent was removed by decantation. The residue was dissolved in 4 ml ofmethylenechloride and 158 ml of triethylamine and 36 ml ofacetylchloride were added to the mixture under ice-cooling. Afterstirring for 1 hour under ice-cooling water was added to the mixture andthe mixture was extracted with chloroform. The organic layer was driedover magnesium sulfate and evaporated in vacuo. The residue was purifiedby silica gel column chromatography (chroloform:methanol=49:1→19:1), togive 304 mg of(2R,4S)-1-{N-(3,5-bistrifluoromethylbenzyl)-N-methyl)-aminocarbonyl-4-{[(2S,4R)-4-benzyloxy-1-acetylpyrrolidin-2-ylcarbonyl]amino}-2-(4-fluoro-2-methylphenyl)piperidineas shown in Table 86.

Examples 314 to 316

The corresponding starting materials were used and treated the samemanner of Examples 313, to give the compounds as shown in Tables 86 and87.

Examples 317 to 318

The corresponding starting materials were used and treated the samemanner of Examples 113(2), to give the compounds as shown in Table 87.

Example 319

In 1.8 ml of toluene was dissolved 98 mg of(2R,4S)-4-amino-1-{N-(3,5-bistrifluoromethylbenzyl)-N-methyl}amino-carbonyl-2-(4-fluoro-2-methylphenyl)piperidine,and added thereto was 24 mg of succinic anhydride and 0.033 ml oftriethylamine, and the mixture was refluxed for 18 hours. The mixturewas cooled down at room temperature, and then was added water. Themixture was extracted with ethyl acetate, the organic layer was driedand concentrated. The residue was purified by thin layer silica gelcolumn chromatography (chloroform:methanol=19:1), to give 79 mg of(2R,4S)-1-{N-(3,5-bistrifluoromethylbenzyl)-N-methyl}aminocarbonyl-4-(2,5-dioxopyrrolino)-2-(4-fluoro-2-methylphenyl)piperidineas shown in Table 87 below.

Examples 320 to 330

The corresponding starting materials were used and treated in the samemanner as in Example 209, to give compounds as shown in Tables 88 to 90below.

Example 331

The corresponding starting materials were used and treated in the samemanner as in Example 113, to give(2R,4S)-1-{N-(3,5-bistrifluoromethylbenzyl)-N-methyl}aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-(ethoxycarbonylmethyl)-piperidineas shown in Table 91 below.

Example 332

In 20 ml of tetrahydrofuran was dissolved 2.03 g of(2R,4S)-1-{N-(3,5-bistrifluoromethylbenzyl)-N-methyl}aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-ethoxycarbonylmethylpiperidine,and added thereto was 450 mg of aluminum lithium hydride underice-cooling, and the mixture was stirred for an hour. Slowly addedthereto was 2 ml of water and after stirring the mixture for 10 minutes,5 ml of a 1M aqueous sodium hydroxide solution was added and the mixturewas further stirred for 10 minutes. Formed white precipitates wereremoved, and diethyl ether and water were added to the filtrate, andlayers were separated. The organic layer was further washed with water,dried, and concentrated under reduced pressure. The residue was purifiedby silica gel column chromatography (hexane:ethyl acetate=4:1→3:2), togive 830 mg of(2R,4S)-1-{N-(3,5-bistrifluoromethylbenzyl)-N-methyl}aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-(2-hydroxyethyl)piperidineas shown in Table 91 below.

Example 333

The corresponding starting material was used and treated in the samemanner as in Example 245, to give(2R,4S)-1-{N-(3,5-bistrifluoromethylbenzyl)-N-methyl}aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-(N-pirazine-2-ylamino)piperidineas shown in Table 91 below.

Example 334

In 2 ml of N,N-dimethylformamide was dissolved 114 mg of(2R,4S)-1-{N-(3,5-bistrifluoromethylbenzyl)-N-methyl}aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-(N-pyrazin-2-ylamino)piperidine,and 10 mg of sodium hydride (40% oil mixture) was added thereto underice-cooling, and after stirring the mixture for 5 minutes, 0.013 ml ofmethyl iodide was added and the mixture was stirred at room temperaturefor 2 hours. To the solution were added water and ethyl acetate, andafter stirring the mixture for 10 minutes, layers were separated. Theorganic layer was washed with brine, dried and concentrated underreduced pressure. The residue was purified by NH silica gel columnchromatography(hexane:ethyl acetate=85:15→1:1), to give 98 mg of(2R,4S)-1-{N-(3,5-bistrifluoromethylbenzyl)-N-methyl}aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-(N-pyrazine-2-yl-N-methylamino)piperidineas shown in Table 91 below.

Example 335

In 40 ml of dichloromethane was dissolved 8.0 g of (2R)-1-{N-(3,5-bistrifluoromethylbenzyl)-N-methyl}aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-oxopiperidine,and added thereto were 10 ml of an ethanol solution of methylamine (35%,about 8M), 2 ml of acetic acid and 4.24 g of sodium triacetoxyborohydride, and the mixture was stirred at room temperature for 16hours. To the solution were added a 2M aqueous sodium carbonate solutionand chloroform, and after stirring the mixture for 30 minutes, layerswere separated. The aqueous layer was further extracted with chloroform,and the combined organic layers were dried and concentrated underreduced pressure. The residue was purified by NH silica gel columnchromatography(hexane:ethyl acetate=2:1), to give a mixture of (a)(2R,4S)-1-{N-(3,5-bistrifluoromethylbenzyl)-N-methyl}aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-methylaminopiperidineand (b)(2R,4R)-1-{N-(3,5-bistrifluoromethylbenzyl)-N-methylaminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-methylaminopiperidine.

(2) The mixture obtained in the above (1) was dissolved in 40 ml ofdichloromethane, and added thereto was 4.4 g ofdi-tert-butyldicarbonate, and the mixture was stirred at roomtemperature for 16 hours. The solution was concentrated under reducedpressure, and the residue was purified by silica gel columnchromatography(hexane:ethyl acetate=10:1), to give 4.2 g of(2R,4S)-1-{N-(3,5-bistrifluoromethylbenzyl)-N-methyl}aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-(tert-butoxycarbonyl-N-methylamino)piperidine.

(3) The compound of the above (2) was treated with 4M hydrochloricacid-ethyl acetate solution, and concentrated under reduced pressure.The residue was recrystallized by a mixed solution of hexane and ethylacetate, to give 3.6 g of(2R,4S)-1-{N-(3,5-bistrifluoromethylbenzyl)-N-methyl}aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-methylaminopiperidinehydrochloride as shown in Table 91 below.

Example 336

(1) 2.12 g of(2R,4S)-4-ethoxycarbonyl-2-(4-fluoro-2-methylphenyl)-4-piperidine wasused and treated in the same manner as in Example 248, to give 3.8 g of(2R,4S)-1-{N-(3,5-bistrifluoromethylbenzyl)-N-methyl}aminocarbonyl-4-ethoxycarbonyl-2-(4-fluoro-2-methylphenyl)piperidine.

(2) The compound of the above (1) was treated in the same manner as inExample 250(1), to give 2.3 g of(2R,4S)-1-{N-(3,5-bistrifluoromethylbenzyl)-N-methyl}amino-4-carboxy-2-(4-fluoro-2-methylphenyl)piperidineas shown in Table 91 below.

Examples 337 to 340

The corresponding starting materials were used and treated in the samemanner as in Example 250 (2), to give compounds as shown in Table 91below.

Example 341

(1) 4-ethoxycarbonyl-2-(4-fluoro-2-methylphenyl)piperidine and thecorresponding starting material were used and treated in the same manneras in Example 248, and purified by silica gel column chromatography(hexane:ethyl acetate=4:1), to give(2R,4S)-1-[N-{1-(S)-(3,5-bistrifluoromethylphenyl)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-ethoxycarbonylpiperidine.

(2) The compound of the above (1) was used and treated in the samemanner as in Example 250 (1), to give(2R,4S)-1-[N-{1-(S)-(3,5-bistrifluoromethylphenyl)ethyl}-N-methyl}aminocarbonyl-4-carboxy-2-(4-fluoro-2-methylphenyl)piperidineas shown in Table 92 below.

Examples 342 to 349

(2R,4S)-1-[N-{1-(S)-(3,5-bistrifluoromethylphenyl)ethyl}-N-methyl]aminocarbonyl-4-carboxy-2-(4-fluoro-2-methylphenyl)piperidineand the corresponding starting materials were used and treated in thesame manner as in Example 250 (2), to give compounds as shown in Table92 below.

Example 350

In 12 ml of tetrahydrofuran was dissolved 1.62 g of(2R,4S)-1-[N-{1-(S)-(3,5-bistrifluoromethylphenyl)ethyl}-N-methyl]aminocarbonyl-4-carboxy-2-(4-fluoro-2-methylphenyl)piperidine,and added dropwise thereto was 2 ml of dimethylsulfide complex of borane(about 10M), and the mixture was stirred at room temperature for 16hours. To the reaction mixture was added 10 ml of methanol and themixture was stirred for 0.5 hours. After the reaction was completed, themixture was concentrated under reduced pressure, and the residue waspurified by silica gel column chromatography (chloroform:methanol=9:1),to give 1.32 g of(2R,4S)-1-[N-{1-(S)-(3,5-bistrifluoromethylphenyl)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-hydroxymethylpiperidineas shown in Table 93 below.

Examples 351 to 352

(2R,4S)-1-[N-{1-(S)-(3,5-bistrifluoromethylphenyl)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-hydroxymethylpiperidineand the corresponding starting materials were used and treated in thesame manner as in Example 209, to give compounds as shown in Table 93below.

Example 353

4-ethoxycarbonyl-2-(4-fluoro-2-methylphenyl)piperidine and thecorresponding starting material were used and treated in the same manneras in Example 341, to give compound(2R,4S)-1-[N-{1-(R)-(3,5-bistrifluoromethylphenyl)ethyl}-N-methyl]aminocarbonyl-4-carboxy-2-(4-fluoro-2-methylphenyl)piperidineas shown in Table 94 below.

Examples 354 to 365

(2R,4S)-1-[N-{1-(R)-(3,5-bistrifluoromethylphenyl)ethyl}-N-methyl]aminocarbonyl-4-carboxy-2-(4-fluoro-2-methylphenyl)piperidineand the corresponding starting materials were used and treated in thesame manner as in Example 250 (2), to give compounds as shown in Tables94 and 95 below.

Example 366

In 2 ml of dichloromethane was dissolved 132 mg of(2R,4S)-1-[N-{1-(R)-(3,5-bistrifluoromethylphenyl)ethyl}-N-methyl]aminocarbonyl-4-carboxy-2-(4-fluoro-2-methylphenyl)piperidine,and added thereto were 0.027 ml of oxalic dichloride and one drop ofN,N-dimethylformamide, and the mixture was stirred at room temperaturefor 2 hours. The reaction mixture was concentrated under reducedpressure. To the residue were added 2.5 ml of tetrahydrofuran and 0.12ml of 2-aminopyrazine and the mixture was stirred at room temperaturefor 16 hours. The reaction mixture was concentrated under reducedpressure, and the residue was purified by NH silica gel columnchromatography (hexane:ethyl acetate=1:1), to give 63 mg of(2R,4S)-1-[N-{1-(R)-(3,5-bistrifluoromethylphenyl)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-(2-pyrazylaminocarbonyl)piperidineas shown in Table 96 below.

Example 367

(2R,4S)-1-[N-{1-(R)-(3,5-bistrifluoromethylphenyl)ethyl}-N-methyl]aminocarbonyl-4-carboxy-2-(4-fluoro-2-methylphenyl)piperidinewas used and treated in the same manner as in Example 350, to give(2R,4S)-1-[N-{1-(R)-(3,5-bistrifluoromethylphenyl)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-hydroxymethylpiperidineas shown in Table 96 below.

Example 368

In a mixture of 20 ml of toluene and 20 ml of acetic acid anhydride wasdissolved 1.07 g of the compound of Example 268, and added thereto 165mg of sodium acetate and the mixture was stirred while being refluxedunder heating for 16 hours. After the reaction mixture was cooled downto room temperature, an aqueous sodium hydrogen carbonate solution wasslowly added thereto until no foam was generated. To the mixture wereadded water and ethyl acetate, and layers were separated. The aqueouslayer was further extracted with ethyl acetate, and the combined organiclayers were dried and concentrated under reduced pressure. The residuewas purified by silica gel column chromatography (hexane:ethylacetate=1:1), to give 980 mg of(2R,4S)-1-{N-(3,5-bistrifluoromethylbenzyl)-N-methyl}aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-acetoxymethylthiopiperidineas shown in Table 97 below.

Example 369

(2R,4S)-4-acetoxymethylthio-1-{N-(3,5-bistrifluoromethylbenzyl)-N-methyl}aminocarbonyl-2-(4-fluoro-2-methylphenyl)piperidinewas used and treated in the same manner as in Example 214, to give(2R,4S)-4-acetoxymethylsulfonyl-1-{N-(3,5-bistrifluoromethylbenzyl)-N-methyl}aminocarbonyl-2-(4-fluoro-2-methylphenyl)piperidineas shown in Table 97 below.

Example 370

In 10 ml of tetrahydrofuran and 5 ml of a 2M aqueous sodium hydroxidesolution was dissolved 200 mg of(2R,4S)-4-acetoxymethylsulfonyl-1-{N-(3,5-bistrifluoromethylbenzyl)-N-methyl}aminocarbonyl-2-(4-fluoro-2-methylphenyl)piperidine,and the mixture was stirred at room temperature for 3 hours. Thereaction mixture was neutralized by 2M hydrochloric acid, and themixture was extracted with ethyl acetate twice. The combined organiclayers were dried and concentrated under reduced pressure, to give 80 mgof(2R,4S)-1-{N-(3,5-bistrifluoromethylbenzyl)-N-methyl}aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-hydroxysulfinylpiperidineas shown in Table 97 below.

Example 371

In 2.5 ml of acetonitrile was dissolved 130 mg of the compound ofExample 261, and added thereto was 0.5 ml of methyl iodide, and themixture was stirred at 50° C. for 2 hours. The reaction mixture wasconcentrated and the residue was washed with diethyl ether, to give 117mg of(2R,4S)-[1-}N-(3,5-bistrifluoromethylbenzyl)-N-methyl}aminocarbonyl-2-(4-fluoro-2-methylphenyl)piperidine-4-yl]dimethylsulfoniumiodide as shown in Table 97 below.

Example 372

In 100 ml of tetrahydrofuran was dissolved 10.7 g of(2R)-1-{N-(3,5-bistrifluoromethylbenzyl)-N-hydroxypropyl}aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-oxopiperidine,and added thereto were 20 ml of pyridine and 20 ml of acetic acidanhydride, and the mixture was stirred at room temperature for S hours.To the reaction mixture were added an aqueous sodium hydrogen carbonatesolution and diethyl ether, and the mixture was stirred for an hour.Layers were separated and after the organic layer was washed with watertwice, it was dried and concentrated under reduced pressure. The residuewas dissolved in 100 ml of ethanol, and added thereto was 1.5g of sodiumborohydride under ice-cooling and the mixture was stirred for 0.5 hours.To the reaction mixture was added an aqueous ammonium chloride solutionand after stirring the mixture for 30 minutes, the solvent was removedby distillation under reduced pressure. To the residue was added waterand the solution was extracted with chloroform twice. The combinedorganic layers were dried and concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography(chloroform:methanol=9:1), to give 9.6 g of(2R,4S)-1-{N-(3-acetoxypropyl)-N-(3,5-bistrifluoromethylbenzyl)}aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-hydroxypiperidineas shown in Table 98 below.

Examples 373 to 376

(2R,4S)-1-{N-(3-acetoxypropyl)-N-(3,5-bistrifluoromethylbenzyl)}aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-hydroxypiperidineand the corresponding starting materials were used and treated in thesame manner as in Example 209, to give compounds as shown in Table 98below.

Example 377

In 5 ml of methanol was dissolved 600 mg of(2R,4S)-1-{N-(3-acetoxypropyl)-N-(3,5-bistrifluoromethylbenzyl)}aminocarbonyl-4-ethylaminocarbonyloxy-2-(4-fluoro-2-methylphenyl)piperidine,and added thereto was 5 ml of a 2M aqueous sodium hydroxide solution,and the mixture was stirred at room temperature for 16 hours. To thereaction mixture was added a 2M aqueous hydrochloric acid solution toneutralize, and the mixture was extracted with chloroform twice. Thecombined organic layers were dried, concentrated under reduced pressureand purified by silica gel column chromatography(chloroform:methanol=9:1), to give 550 mg of(2R,4S)-1-{N-(3,5-bistrifluoromethylbenzyl)-N-(3-hydroxypropyl)}aminocarbonyl-4-ethylaminocarbonyloxy-2-(4-fluoro-2-methylphenyl)piperidineas shown in Table 99 below.

Examples 378 to 381

The corresponding starting materials were used and treated in the samemanner as in Example 377 to give compounds as shown in Table 99 below.

Example 382

(2R,4S)-1-{N-(3,5-bistrifluoromethylbenzyl)-N-(3-hydroxypropyl)}aminocarbonyl-4-thiomorpholinocarbonyloxy-2-(4-fluoro-2-methylphenyl)piperidinewas used and treated in the same manner as in Example 213, to give(2R,4S)-1-{N-(3,5-bistrifluoromethylbenzyl)-N-(3-hydroxypropyl)}aminocarbonyl-4-(1-oxothiomorpholino)carbonyloxy-2-(4-fluoro-2-methylphenyl)piperidineas shown in Table 99 below.

Example 383

(1)(2R,4S)-1-[N-acetoxypropyl-N-(3,5-bistrifluoromethylbenzyl)}aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-hydroxypiperidinewas used and treated in the same manner as in Example 254 (1) and (2),to give(2R,4S)-1-{N-acetoxypropyl-N-(3,5-bistrifluoromethylbenzyl)}aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-acetylthiopiperidine.

(2) The compound of the above (1) was used and treated in the samemanner as in Example 257, to give(2R,4S)-1-{N-(3,5-bistrifluoromethylbenzyl)-N-hydroxypropyl}aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-(2-propylthio)piperidine.

(3) The compound of the above (2) was used and treated in the samemanner as in Example 213, to give(2R,4S)-1-{N-(3,5-bistrifluoromethylbenzyl)-N-hydroxypropyl}aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-(propane-2-sulfinyl)piperidineas shown in Table 99 below.

Example 384

(2R,4S)-1-{N-(3,5-bistrifluoromethylbenzyl)-N-hydroxypropyl}aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-(2-propylthio)piperidinewas used and treated in the same manner as in Example 214, to give(2R,4S)-1-{N-(3,5-bistrifluoromethylbenzyl)-N-hydroxypropyl}aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-(propane-2-sulfonyl)piperidineas shown in Table 99 below.

Example 385

148 mg of(2R,4S)-2-(4-fluoro-2-methylphenyl)-4-(2-hydroxyethylaminocarbonyloxy)piperidineand the corresponding starting material were used and treated in thesame manner as in Reference Example 6, to give 36 mg of(2R,4S)-1-{N-(3,5-dimethylbenzyl)-N-methyl}aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-(2-hydroxyethylaminocarbonyloxy)piperidineas shown in Table 100 below.

Example 386

The corresponding starting materials were used and treated in the samemanner as in Example 385, to give(2R,4S)-1-{N-(3,5-dichlorobenzyl)-N-methyl}aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-(2-hydroxyethylaminocarbonyloxy)piperidineas shown in Table 100 below.

Example 387

In 10 ml of tetrahydrofuran was dissolved 676 mg of(2R,4S)-2-(4-fluoro-2-methylphenyl)-4-(2-acetoxyethylaminocarbonyloxy)piperidinehydrochloride, and added thereto was 0.28 ml of triethylamine and themixture was stirred for 30 minutes. To the reaction mixture was added330 mg of 1,1′-carbonyldiimidazole, and the mixture was stirred at 65°C. for 2 hours. The solvent was removed by distillation under reducedpressure, and the residue was dissolved in 5 ml of dichloromethane. Themixture was washed with water and saturated brine and dried. The mixturewas evaporated in vacuo, and the residue was dissolved in 5 ml ofacetonitrile. To the solution was added 1 ml of methyl iodide, and themixture was stirred at 60° C. for 2 hours. The solvent was removed bydistillation under reduced pressure. The residue was dissolved in 20 mlof tetrahydrofuran, and added thereto were 600 mg ofN-{1-(3,5-bistrifluoromethylphenyl)-2-hydroxyethyl}-N-methylamine and0.5 ml of triethylamine, and the mixture was stirred at 70° C. for 3hours. To the reaction mixture were added ethyl acetate and water, andlayers were separated. The organic layer was dried and concentratedunder reduced pressure. The residue was purified by silica gel columnchromatography (chloroform:methanol=19:1), to give 780 mg of a mixtureof the compounds (a)(2R,4S)-4-(2-acetoxyethylaminocarbonyloxy)-1-[N-{1-(S)-(3,5-bistrifluoromethylphenyl)-2-hydroxyethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-methylphenyl)piperidineand (b)(2R,4S)-4-(2-acetoxyethylaminocarbonyloxy)-1-[N-{1-(R)-(3,5-bistrifluoromethylphenyl)-2-hydroxyethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-methylphenyl)piperidine,as shown in Table 101 below.

Example 388

In 2 ml of methanol was dissolved 122 mg of the compound of Example 387,and added thereto was 1 ml of a 2M aqueous sodium hydroxide solution,and the mixture was stirred at room temperature for 16 hours. Thereaction mixture was neutralized with a 6M aqueous hydrochloric acidsolution, and the solvent was removed by distillation under reducedpressure. To the residue were added chloroform and water and layers wereseparated. The aqueous layer was further extracted with chloroform, andthe combined organic layers were dried and concentrated under reducedpressure. The residue was vacuum dried, to give 88 mg of a mixture ofthe compounds (a)(2R,4S)-1-[N-{1-(S)-(3,5-bistrifluoromethylphenyl)-2-hydroxyethyl)-N-methyl]aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-(2-hydroxyethylaminocarbonyloxy)piperidineand (b)(2R,4S)-1-[N-{1-(S)-(3,5-bistrifluoromethylphenyl)-2-hydroxyethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-(2-hydroxyethylaminocarbonyloxy)piperidineas shown in Table 101 below.

Example 389

(1) In 50 ml of dichloromethane was dissolved 4.92 g of(2R,4S)-1-{N-(3,5-bistrifluoromethylbenzyl)-N-methyl}aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-hydroxypiperidine,and 2.43 g of carbodiimidazole was added to the solution at roomtemperature, and the mixture was stirred for 1.5 hours. To the reactionmixture was added water and layers were separated with dichloromethane.The organic layer was washed with saturated brine, dried and the solventwas removed by distillation under reduced pressure, to give 5.99 g of(2R,4S)-1-{N-(3,5-bistrifluoromethylbenzyl)-N-methyl}aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-(1-imidazolylcarbonyloxy)piperidine.

(2) In a toluene solution (12 ml) of N,N-dimethylformamide (5 ml) wasdissolved 1.17 g of the compound of the above (1), and added thereto was0.925 ml of ethyl nipecotate at room temperature, and the mixture wasstirred overnight. To the reaction mixture was added ethyl acetate, andthe mixture was washed with water and saturated brine and dried. Thesolvent was removed by distillation under reduced pressure and theresidue was purified by silica gel column chromatography(chloroform:methanol=39:1), to give 1.24 g of(2R,4S)-1-{N-(3,5-bistrifluoromethylbenzyl)-N-methyl}aminocarbonyl-4-(4-ethoxycarbonylpiperidinocarbonyloxy)-2-(4-fluoro-2-methylphenyl)piperidineas shown in Table 102.

Example 390

In 15 ml of ethanol was dissolved 1.08 g of the compound of Example 389,and added thereto 4.8 ml of 1M potassium hydroxide-ethanol solution atroom temperature. After the temperature of the mixture was raised to 50°C., the mixture was stirred for 3 hours. To the reaction mixture wasadded a 2M aqueous hydrochloric acid solution and ethanol was removed bydistillation under reduced pressure. Water and chloroform were addedthereto and layers were separated with chloroform. The organic layer waswashed with saturated brine and dried, and the solvent was removed bydistillation under reduced pressure. The residue was purified by silicagel column chromatography (chloroform:methanol=9:1), to give 1.05 g of(2R,4S)-1-{N-(3,5-bistrifluoromethylbenzyl)-N-methyl}aminocarbonyl-4-(4-carboxypiperidinocarbonyloxy)-2-(4-fluoro-2-methylphenyl)piperidineas shown in Table 102 below.

Example 391

In 1 ml of dichloromethane were dissolved 64.8 mg of the compound ofExample 390 and 18.6 mg of ethanolamine, and added thereto at roomtemperature was 48.6 mg of carbodiimidazole, and the mixture was stirredat room temperature overnight. A saturated aqueous ammonium chloridesolution was added thereto and the mixture was extracted withdichloromethane. The organic layer was dried and the solvent was removedby distillation under reduced pressure. The residue was purified bysilica gel column chromatography (chloroform:methanol=19:1), to give17.8 mg of(2R,4S)-1-{N-(3,5-bistrifluoromethylbenzyl)-N-methyl}aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-{4-(2-hydroxyethylaminocarbonyl)piperidinocarbonyloxy}piperidineas shown in Table 102.

Examples 392 to 398

The compound of Example 390 and the corresponding starting materialswere used and treated in the same manner as in Example 391, to givecompounds as shown in Tables 102 to 103 below.

Example 399

(1) In 12 ml of toluene was dissolved 1.17 g of(2R,4S)-1-{N-(3,5-bistrifluoromethylbenzyl)-N-methyl}aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-(1-imidazolylcarbonyloxy)piperidine,and added thereto at room temperature was 1.14 g of4-amino-1-benzylpiperidine, and the mixture was stirred for 3 days. Tothe reaction mixture was added ethyl acetate, and the mixture was washedwith water and saturated brine and dried. The solvent was removed bydistillation under reduced pressure. The residue was purified by silicagel column chromatography (chloroform:methanol=19:1), to give 0.89 g of(2R,4S)-1-{N-(3,5-bistrifluoromethylbenzyl)-N-methyl}aminocarbonyl-4-(1-benzylpiperidine-4-yl)aminocarbonyloxy-2-(4-fluoro-2-methylphenyl)piperidine.

(2) In 10 ml of methanol was dissolved 890 mg of the compound of theabove (1), and added thereto were 400 mg of palladium carbon and onedrop of concentrated hydrochloric acid, and the mixture was stirred inhydrogen atmosphere for 4.5 hours. After the reaction mixture wasfiltered and the filtrate was evaporated in vacuo, the residue wascrystallized (ethyl acetate-hexane), to give 802 mg of(2R,4S)-1-{N-(3,5-bistrifluoromethylbenzyl)-N-methyl}aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-(4-piperidinyl)aminocarbonyloxypiperidine.

(3) In 2 ml of dichloromethane was dissolved 14.2 mg of3-hydroxy-3-methylbutanoic acid, and added thereto at room temperaturewas 21.1 mg of carbodiimidazole, and the mixture was stirred at roomtemperature overnight. To the reaction mixture was added 61.9 mg of thecompound of the above (2), and the mixture was further stirredovernight. To the reaction mixture was added water, and the mixture wasextracted with chloroform. The organic layer was dried and the solventwas removed by distillation under reduced pressure. The residue waspurified by silica gel column chromatography (chloroform:methanol=19:1),to give 57.5 mg of(2R,4S)-1-{N-(3,5-bistrifluoromethylbenzyl)-N-methyl}aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-{1-(3-hydroxy-3-methylbutyryl)piperidine-4-yl}aminocarbonyloxypiperidineas shown in Table 104 below.

Examples 400 to 402

The compound of Example 399 (2) and the corresponding starting materialswere treated in the same manner as in Example 399 (3), to give compoundsas shown in Table 104 below.

Example 403

(2R,4S)-1-{N-(3,5-bistrifluoromethylbenzyl)-N-ethyl}aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-hydroxypiperidineobtained by treating the compound of Reference Example 11 (2) in thesame manner as in Example 2 was treated in the same manner as in Example209, to give a compound as shown in Table 105 below.

Example 404

The corresponding starting material was treated in the same manner as inExample 209, to give a compound as shown in Table 105 below.

Example 405

The compound of Example 404 was treated in the same manner as in Example213, to give a compound as shown in Table 105 below.

Example 406

The compound of Example 404 was treated in the same manner as in Example214, to give a compound as shown in Table 105 below.

Examples 407 to 413

The corresponding starting materials were treated in the same manner asin Example 257, to give compounds as shown in Tables 106 to 107 below.

Example 414

In 50 ml of methanol was dissolved 1.17 g of(2R,4S)-4-acetylthio-1-{N-(3,5-bistrifluoromethylbenzyl)-N-methyl}aminocarbonyl-2-(4-fluoro-2-methylphenyl)piperidine,and added thereto at room temperature was 1.17 g of tert-butyl2-bromoethylcarbamate. Subsequently, 25 ml of a 1M aqueous sodiumhydroxide solution was added dropwise thereto. The reaction mixture wasstirred for 5 minutes, and the solvent was removed by distillation underreduced pressure, and the mixture was extracted with dichloromethane,washed with saturated brine and dried. The solvent was removed bydistillation under reduced pressure. The residue was purified by silicagel column chromatography (hexane:ethyl acetate=2:1), to give 710 mg of(2R,4S)-1-{N-(3,5-bistrifluoromethylbenzyl)-N-methyl}aminocarbonyl-4-(2-tert-butoxycarbonylaminoethylthio)-2-(4-fluoro-2-methylphenyl)piperidineas shown in Table 107 below.

Example 415

(1) To 681 mg of the compound of Example 414 was added 2 ml of 4Mhydrochloric acid-ethyl acetate solution under ice-cooling, and themixture was stirred at room temperature for an hour. The solvent wasremoved by distillation, and a saturated aqueous sodium bicarbonatesolution was added and the mixture was extracted with chloroform. Theorganic layer was dried and the solvent was removed by distillationunder reduced pressure, to give 612 mg of(2R,4S)-4-(2-aminoethylthio)-1-{N-(3,5-bistrifluoromethylbenzyl)-N-methyl}aminocarbonyl-2-(4-fluoro-2-methylphenyl)piperidinehydrochloride as shown in Table 107 below.

(2) In 1 ml of N,N-dimethylformamide were dissolved 55.2 mg of thecompound of the above (1) and 9.1 mg of glycolic acid, and added theretowere 24.9 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride and 19.9 ml of N-hydroxybenzotriazole monohydrate, and themixture was stirred at room temperature overnight. Ethyl acetate wasadded thereto and the mixture was washed with water and saturated brine,dried and the solvent was removed by distillation under reducedpressure. The residue was purified by silica gel column chromatography(chloroform:methanol=19:1), to give 28.8 mg of(2R,4S)-1-{N-(3,5-bistrifluoromethylbenzyl)-N-methyl}aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-{2-(1-hydroxyacetylamino)ethylthio}piperidineas shown in Table 107 below.

Examples 416 to 419

The compound of Example 415 (1) and the corresponding starting materialswere treated in the same manner as in Example 415 (2), to give compoundsas shown in Table 108 below.

Example 420

In 1 ml of N,N-dimethylformamide was dissolved 55.2 mg of the compoundof Example 415 (1), and 9.1 mg of carbodiimidazole was added thereto,and the mixture was stirred at room temperature for 3 hours. To thereaction mixture was added ethyl acetate, and the mixture was washedwith water and brine and dried. The solvent was removed by distillation,and the residue was dissolved in 1 ml of acetonitrile, and 0.025 ml ofmethyl iodide was added thereto. The mixture was stirred at 50° C.overnight. Subsequently, 0.025 ml of methyl iodide was further added andthe mixture was stirred at the same temperature overnight. Afterremoving N,N-dimethylformamide and methyl iodide by distillation underreduced pressure, 1 ml of toluene and 0.040 ml of morpholine were added,and the mixture was stirred at room temperature for 5 days. To thereaction mixture was added water, and the mixture was extracted withethyl acetate. The organic layer was dried and the solvent was removedby distillation under reduced pressure. The residue was purified bysilica gel column chromatography (chloroform:methanol=19:1), to give38.0 mg of(2R,4S)-1-{N-(3,5-bistrifluoromethylbenzyl)-N-methyl}aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-(2-morpholinocarbonylaminoethylthio)piperidineas shown in Table 108 below.

Example 421

The compound of Example 415 (1) and the corresponding starting materialwere treated in the same manner as in Example 420, to give(2R,4S)-1-{N-(3,5-bistrifluoromethylbenzyl)-N-methyl}aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-{2-(2-hydroxymethylamino)carbonylaminoethylthio}piperidineas shown in Table 108 below.

Example 422

The corresponding starting materials were used and treated in the samemanner as in Example 213, to give(2R,4S)-1-{N-(3,5-bistrifluoromethylbenzyl)-N-methyl}aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-{4-(2-methylsulfinylethylaminocarbonyl)piperidinocarbonyloxy}-piperidineas shown in Table 108 below.

Example 423

The corresponding starting materials were used and treated in the samemanner as in Example 214, to give(2R,4S)-1-{N-(3,5-bistrifluoromethylbenzyl)-N-methyl}aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-{4-(3-methylsulfonylpropylaminocarbonyl)piperidinocarbonyloxy}-piperidineas shown in Table 108 below.

Examples 424 to 425

The corresponding starting materials were used and treated in the samemanner as in Example 209, to give compounds as shown in Table 109 below.

Example 426

In 1.5 ml of dichloromethane was dissolved 82.0 mg of(2R,4S)-1-{N-(3,5-bistrifluoromethylbenzyl)-N-methyl}aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-(2-methylthioethylaminocarbonyloxy)piperidine,and added thereto at room temperature 99.5 mg of m-chloroperbenzoic acidand the mixture was stirred for an hour. To the reaction mixture wasadded a saturated aqueous sodium hydrogen carbonate solution, and layerswere separated with ethyl acetate. The organic layer was washed withsaturated brine and dried, and the solvent was removed by distillationunder reduced pressure. The residue was purified by silica gel columnchromatography (chloroform:methanol=19:1), to give 48.6 mg of(2R,4S)-1-{N-(3,5-bistrifluoromethylbenzyl)-N-methyl}aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-(2-methylsulfonylethylaminocarbonyloxy)piperidineas shown in Table 109 below.

Example 427

(2R,4S)-1-{N-(3,5-bistrifluoromethylbenzyl)-N-methyl}aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-(3-methylthiopropylaminocarbonyloxy)piperidinewas treated in the same manner as in Example 426, to give(2R,4S)-1-{N-(3,5-bistrifluoromethylbenzyl)-N-methyl}aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-(3-methylsulfonylpropylaminocarbonyloxy)piperidineas shown in Table 109 below.

Examples 428 to 431

The corresponding starting materials were treated in the same manner asin Example 169, to give compounds as shown in Table 110 below.

Examples 432 to 433

The corresponding starting materials were treated in the same manner asin Example 213, to give compounds as shown in Table 111 below.

Examples 434 to 435

The corresponding starting materials were treated in the same manner asin Example 214, to give compounds as shown in Table 111 below.

Example 436

In 2.8 ml of acetonitrile was dissolved 130 mg of imidazole-1-carboxylicacid N-(3,5-bistrifluoromethylbenzyl)-N-(2-methoxyethyl)amide, and addedthereto was 411 μl of methyl iodide, and the mixture was stirred at 50°C. for 3 hours. The reaction mixture was concentrated under reducedpressure. The residue was suspended in 2.7 ml of dichloromethane, andadded thereto were 89 mg of(2R,4S)-2-(4-fluoro-2-methylphenyl)-4-(2-hydroxyethylaminocarbonyloxy)piperidineand 50 μl of triethylamine, and the mixture was stirred at roomtemperature for 20 hours. To the reaction mixture was added a 5% aqueouscitric acid solution, and the mixture was extracted with chloroform. Theorganic layer was dried over magnesium sulfate, and concentrated underreduced pressure. The residue was purified by thin-layer silica gelchromatography (chloroform:methanol=19:1), to give 63 mg of(2R,4S)-1-{N-(3,5-bistrifluoromethylbenzyl)-N-(2-methoxyethyl)}aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-(2-hydroxyethylaminocarbonyloxy)piperidineas shown in Table 112 below.

Example 437

In 2.7 ml of dichloromethane was dissolved 94 mg of2-(4-fluoro-2-methoxyphenyl)-4-(2-hydroxyethylaminocarbonyloxy)piperidine,and added thereto were 163 mg of3-[(3,5-bistrifluoromethylbenzyl)-methylcarbamoyl]-1-methyl-3H-imidazol-1-iumiodide and 50 μl of triethylamine, and the mixture was stirred at roomtemperature for 18 hours. To the reaction mixture was added distilledwater and the mixture was extracted with chloroform. The organic layerwas dried over magnesium sulfate and concentrated under reducedpressure. The residue was purified by thin-layer silica gelchromatography (chloroform:methanol=19:1), to give 84 mg of1-{N-(3,5-bistrifluoromethylbenzyl)-N-methyl}aminocarbonyl-2-(4-fluoro2-methoxyphenyl)-4-(2-hydroxyethylaminocarbonyloxy)piperidine as shownin Table 112 below.

Example 438

In 5.2 ml of acetonitrile was dissolved 201 mg of imidazole-1-carboxylicacid N-[(1S)-1-(3,5-bistrifluoromethylphenyl)ethyl]-N-methylamide, andadded thereto was 137 μl of methyl iodide. After the mixture was stirredat 50° C. for 3 hours, the reaction mixture was concentrated underreduced pressure. The residue was dissolved in 4.5 ml ofdichloromethane, and added thereto was 132 mg of4-(2-hydroxyethylcarbamoyloxy)-2-phenylpiperidine and 84 μl oftriethylamine, and the mixture was stirred at room temperature for 18hours. To the reaction mixture was added a 5% aqueous citric acidsolution, and the mixture was extracted with chloroform, and the organiclayer was dried and concentrated under reduced pressure. The residue waspurified by thin-layer silica gel chromatography(chloroform:acetone=4:1), to give 75 mg of(2R,4R)-1-[N-}(S)-1-(3,5-bistrifluoromethylphenyl)ethyl}-N-methyl]aminocarbonyl-4-(2-hydroxyethylaminocarbonyloxy)-2-phenylpiperidineas shown in Table 112 below.

Example 439

(1) In 3 ml of acetonitrile was dissolved 127 mg of1-(3,5-bistrifluoromethylphenyl)ethyl imidazole-1-carboxylate, and addedthereto was 448 μl of methyl iodide. The mixture was stirred at 50° C.for 3 hours, and the reaction mixture was concentrated. The residue wassuspended in 2.7 ml of dichloromethane, and added thereto were 102 mg of2-[(2R,4S)-2-(4-fluoro-2-methylphenyl)piperidine-4-yloxycarbonylamino]ethylacetate and 50 μl of triethylamine, and the mixture was stirred at roomtemperature for 18 hours. To the reaction mixture was added distilledwater and the mixture was extracted with chloroform. The organic layerwas dried and concentrated. The residue was purified by thin-layersilica gel chromatography (hexane:ethyl acetate=1:1), to give 43 mg of(2R,4S)-4-(2-acetoxyethylaminocarbonyloxy)-1-{(S)-1-(3,5-bistrifluoromethylphenyl)ethyl}oxycarbonyl-2-(4-fluoro-2-methylphenyl)piperidine.MS(m/z):623[M⁺+1]

(2)In a mixture of 0.9 ml of tetrahydrofuran and 0.1 ml of methanol wasdissolved 43 mg of the compound of the above (1), and added thereto was103 μl of a 1M aqueous sodium hydroxide solution, and the mixture wasstirred at room temperature for an hour. To the reaction mixture wasadded distilled water and the mixture was extracted with ethyl acetate.The organic layer was dried and concentrated. The residue was purifiedby thin-layer silica gel chromatography (chloroform:methanol=19:1), togive 37 mg of(2R,4S)-1-{(S)-1-(3,5-bistrifluoromethylphenyl)ethyl}oxycarbonyl-2-(4-fluoro-2-methylphenyl)-4-(2-hydroxyethylaminocarbonyloxy)piperidineas shown in Table 112 below.

Example 440

In 2.4 ml of N,N-dimethylformamide was dissolved 50 mg of(2R,4S)-2-(4-fluoro-2-methyl)phenyl-4-hydroxypiperidine, and addedthereto under nitrogen atmosphere at room temperature were 0.044 ml oftriethylamine and 99.3 mg ofN-(3,5-bistrifluoromethylbenzyl)-N-methylaminocarbonylchloride. Thereaction mixture was stirred at room temperature for 21 hours. Thereaction mixture was poured into water, and the mixture was extractedwith ethyl acetate twice. The organic layers were combined and washedwith saturated brine, dried and concentrated. The residue was purifiedby silica gel column chromatography (hexane:ethyl acetate=2:1→1:2), togive 128 mg of(2R,4S)-1-{N-(3,5-bistrifluoromethylbenzyl)-N-methyl}aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-hydroxypiperidineas shown in Table 113 below.

Example 441

In 2.0 ml of dichloromethane was dissolved 560 mg of(2R,4S)-1-{N-(3,5-bistrifluoromethylbenzyl)-N-methyl}aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-hydroxypiperidine,and added thereto under nitrogen atmosphere under ice-cooling, 1.5 ml ofdichloromethane solution containing 0.22 ml of pyridine and 0.314 ml ofphenyl chloroformate. The reaction mixture was stirred at a temperatureof 0° C. to 5° C. for 3.5 hours, and further stirred at room temperaturefor 16 hours. The reaction mixture was poured into water and extractedby adding dichloromethane twice. The organic layers were combined andwashed with a 1M aqueous hydrochloric acid solution twice, and wasfurther washed with saturated brine. The organic layer was dried andconcentrated. The residue was dissolved in 11 ml ofN,N-dimethylformamide, and added thereto under nitrogen atmosphere andat room temperature was 0.274 ml of ethanolamine, and the mixture wasstirred at 60° C. for 26 hours. The reaction mixture was poured intowater and extracted by adding ethyl acetate twice. The organic layerswere combined and washed with saturated brine, dried and concentrated.The residue was purified by silica gel column chromatography(chloroform:methanol=39:1), to give 493 mg of(2R,4S)-1-{N-(3,5-bistrifluoromethylbenzyl)-N-methyl}aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-(2-hydroxyethylaminocarbonyloxy)piperidineas shown in Table 113 below.

Example 442

In 8 ml of dichloromethane was dissolved 1.0 g of(2R)-4-amino-1-{N-(3,5-bistrifluoromethylbenzyl)-N-methyl}aminocarbonyl-2-(4-fluoro-2-methylphenyl)piperidine,and added thereto were 0.31 ml of triethylamine and 466 mg ofdi-tert-butyloxycarbonate, and the mixture was stirred at roomtemperature for 16 hours. To the reaction mixture was added water andthe mixture was extracted with dichloromethane twice. The organic layerswere combined and washed with saturated brine, dried and concentrated.The residue was purified by silica gel column chromatography(hexane:ethyl acetate=4:1), to give 481 mg of (a)(2R,4R)-1-{N-(3,5-bistrifluoromethylbenzyl)-N-methyl}aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-tert-butoxycarbonylaminopiperidineand 516 mg of (b)(2R,4S)-1-{N-(3,5-bistrifluoromethylbenzyl)-N-methyl}aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-tert-butoxycarbonylaminopiperidineas shown in Table 113 below.

Example 443

In 3.5 ml of ethyl acetate was dissolved 700 mg of(2R,4S)-1-{N-(3,5-bistrifluoromethylbenzyl)-N-methyl}aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-tert-butoxycarbonylaminopiperidine,and added thereto under ice-cooling was 3.5 ml of 4M hydrochloricacid-ethyl acetate solution, and the mixture was stirred underice-cooling for 30 minutes. The solvent was removed by distillation, andadded to the residue was ethyl acetate and subjected to filtration. Tothe collected materials were added chloroform and a 2M aqueous sodiumhydroxide solution and layers were separated. The aqueous layer wasextracted with chloroform. The combined organic layers were dried andconcentrated, to give 489 mg of(2R,4S)-4-amino-1-{N-(3,5-bistrifluoromethylbenzyl)-N-methyl}aminocarbonyl-2-(4-fluoro-2-methylphenyl)piperidineas shown in Table 113 below.

Examples 444 to 449

The corresponding starting materials were used and treated in the samemanner as in Example 138, to give compounds as shown in Table 114 below.

Examples 450 to 451

The corresponding starting materials were used and treated in the samemanner as in Example 102 (1), to give compounds as shown in Table 114below.

Examples 452 to 469

The corresponding starting materials were used and treated in the samemanner as in Example 250 (2), to give compounds as shown in Tables 115to 117 below.

Example 470

In 1 ml of dichloromethane was dissolved 52.8 mg of(2R,4S)-4-amino-1-{N-(3,5-bistrifluoromethylbenzyl)-N-methyl}amino-carbonyl-2-(4-fluoro-2-methylphenyl)piperidinehydrochloride, and added thereto at room temperature was 0.017 ml oftriethylamine and 24.3 mg of 1,1-carbodiimidazole, and the mixture wasstirred for 30 minutes. The reaction mixture was added water and themixture was extracted with dichloromethane. The organic layers werewashed with saturated brine, dried and concentrated. In 1 ml ofacetonitrile was dissolved the residue, and added 0.025 ml of methyliodide, and the mixture was stirred at 60° C. over night. The reactionmixture was concentrated, and in 1 ml of toluene-acetonitrile (7:3)solution was dissolved the residue, and added 24.4 mg of ethanolamine,and the mixture was stirred at room temperature for 30 minutes. To thereaction mixture was added water, and the mixture was extracted withethyl acetate. The organic layer was dried and concentrated. The residuewas purified by silica gel column chromatography(chloroform:methanol=9:1), to give 53.1 mg of(2R,4S)-1-{N-(3,5-bistrifluoromethylbenzyl)-N-methyl}aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-(2-hydroxyethylamino)piperidineas shown in Table 118 below.

Examples 471 to 480

The corresponding starting materials were used and treated in the samemanner as in Example 470, to give compounds as shown in Tables 118 to119 below.

Example 481

In 10 ml of dichloromethane was dissolved 490 mg of(2R)-1-{N-(3,5-bistrifluoromethylbenzyl)-N-methyl}amino-carbonyl-2-(4-fluoro-2-methylphenyl)-4-oxopiperidineand 312 mg of 2-(2-aminoethylamino)ethanol, and added thereto at roomtemperature were 0.086 ml of acetic acid and 669 mg of sodiumtriacetoxyborohydride, and the mixture was stirred overnight. To thereaction mixture was added water, and extracted with chloroform. Theorganic layer was washed with saturated brine, dried and concentrated,to give 581 mg of(2R,4RS)-1-{N-(3,5-bistrifluoro-methylbenzyl)-N-methyl}aminocarbonyl-2-(4-fluoro-2-methyl-phenyl)-4-{2-(2-hydroxyethylamino)ethylamino}piperidine[(2R,4S):(2R,4R)=74:26]. In 2 ml of dichloromethane was dissolved 116 mgof(2R,4RS)-1-{N-(3,5-bistrifluoromethylbenzyl)-N-methylaminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-{2-(2-hydroxyethylamino)ethylamino}piperidine,and added thereto at room temperature was 39 mg of 1,1-carbodiimidazole,and the mixture was stirred for 40 minutes. To the reaction mixture wasadded water, and the mixture was extracted with chloroform. The organiclayers were washed with saturated brine, dried and concentrated. Theresidue was purified by silica gel column chromatography(chloroform:methanol=9:1), to give (a) 75.5 mg of(2R,4S)-1-[N-(3,5-bistrifluoromethylbenzyl)-N-methyl}aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-[3-(2-hydroxyethyl)-2-oxoimidazolidine-1-yl]piperidineand give (b) 22.6 mg of(2R,4R)-1-{N-(3,5-bistrifluoromethylbenzyl)-N-methyl}aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-(3-(2-hydroxyethyl)-2-oxoimidazolidine-1-yl]piperidineas shown in Table 120 below.

Examples 482 to 486

The corresponding starting materials were used and treated in the samemanner as in Example 481, to give compounds as shown in Tables 120 to122 below.

Example 487

In 1 ml of dichloromethane was dissolved 12.4 ml of ethylene glycol, andadded thereto at room temperature was 32.4 mg of 1,1-carbodiimidazole.The mixture was stirred at room temperature for 7.5 hours, and to themixture were added 52.8 mg of(2R,4S)-4-amino-1-{N-(3,5-bistrifluoromethylbenzyl)-N-methyl}-aminocarbonyl-2-(4-fluoro-2-methylphenyl)piperidinehydrochloride and 0.021 ml of triethylamine. The mixture was stirred for4 days, and the reaction mixture was concentrated. The residue waspurified by silica gel column chromatography (chloroform:methanol=9:1),to give 16.4 mg of(2R,4S)-1-{N-(3,5-bistrifluoromethylbenzyl)-N-methyl}-amino-carbonyl-2-(4-fluoro-2-methylphenyl)-4-(2-hydroxyethyloxycarbonylamino)-piperidineas shown in Table 123 below.

Example 488

(1) In 3 ml of dichloromethane was dissolved 58 mg of triphosgene, andadded dropwise thereto under −60° C. was 2 ml dichloromethane solutioncontaining 138 mg ofN-{2-methoxy-5-(5-trifluoromethyltetrazole-1-yl)benzyl)-N-methylamineand 0.201 ml of triethylamine, and then the mixture was warmed up at 0°C. The mixture was concentrated, and in 2 ml dichloromethane wasdissolved the residue. To the mixture was added dropwise 2 ml ofdichloromethane solution containing 135 mg of(2R,4S)-4-(2-acetyloxyethylaminocarbonyloxy)-2-(4-fluoro-2-methylphenyl)-piperidineand 0.084 ml of triethylamine, and the mixture was stirred at roomtemperature for one day. To the reaction mixture was added water, andthe mixture was extracted with chloroform. The organic layer was driedover magnesium sulfate and concentrated. The residue was purified bythin layer silica gel column chromatography (chloroform:acetone=10:1),to give 44 mg of(2R,4S)-4-(2-acetyloxyethylaminocarbonyloxy)-1-[N-{2-methoxy-5-(5-trifluoromethyltetrazole-1-yl)benzyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-methylphenyl)piperidine.MS(m/z):652[M⁺+1]

(2) In 0.9 ml of the mixture solution (tetrahydro-furan:methanol=8:1)was dissolved 44 mg of(2R,4S)-4-(2-acetyloxyethylaminocarbonyloxy)-1-[N-{2-methoxy-5-(5-trifluoromethyltetrazole-1-yl)benzyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-methylphenyl)piperidine,and added thereto was 0.101 ml of a 1 M aqueous sodium hydroxidesolution, and the mixture was stirred at room temperature for 6 hours.To the reaction mixture was added water, and the mixture was extractedwith ethyl acetate. The organic layers were dried over magnesium sulfateand concentrated. The residue was purified by thin layer silica gelcolumn chromatography (chloroform:methanol=19:1), to give 36 mg of(2R,4S)-1-[N-{2-methoxy-5-(5-trifluoromethyltetrazole-1-yl)benzyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-(2-hydroxyethylaminocarbonyloxy)piperidineas shown in Table 124 below.

Reference Example 1

To Grignard reagent prepared from 14.2 g of magnesium, 93.1 g of2-bromo-5-fluorotoluene and 500 ml of tetrahydrofuran was added dropwise50 ml of 4-methoxypyridine at −20° C. under nitrogen atmosphere. Aftercompletion of dripwise addition, the mixture was stirred at the sametemperature for 20 minutes. Further, the reaction mixture was cooleddown to −50° C., and 85 ml of benzylchlorocarbonate was added dropwise,while keeping the temperature at −40° C. or below. After completion ofdropwise addition, the temperature of the reaction mixture was slowlyraised, 200 g of ice was added thereto at −15C, and the mixture wasstirred for 30 minutes. Further, 200 ml of a 5M aqueous citric acidsolution was added thereto and the mixture was stirred at roomtemperature for an hour. From the reaction mixture tetrahydrofuran wasremoved by distillation under reduced pressure. To the residue was added200 ml of ethyl acetate and the mixture was extracted twice. The organiclayers were combined and washed with an aqueous sodium hydrogencarbonate solution and saturated brine, dried over magnesium sulfate,and the solvent was removed by distillation under reduced pressure. Theresidue was collected by filtration and washed with isopropyl ether, togive 146.5 g of1-benzyloxycarbonyl-2-(4-fluoro-2-methylphenyl)-4-oxo-3,4-dihydro-2H-pyridineas shown in Table 125 below.

Reference Example 2

In 4600 ml of acetic acid was dissolved 190 g of1-benzyloxycarbonyl-2-(4-fluoro-2-methylphenyl)-4-oxo-3,4-dihydro-2H-pyridine,and added thereto was 91 g of zinc powder and the mixture was stirred atroom temperature for 24 hours. From the reaction mixture was removedinsoluble matters by filtration, and the solvent was removed bydistillation under reduced pressure. To the residue was added 400 ml ofethyl acetate, and the mixture was washed with an aqueous sodiumhydrogen carbonate solution and saturated brine, and dried overmagnesium sulfate. The solvent was removed by distillation under reducedpressure, and the residue was purified by silica gel columnchromatography (ethyl acetate:hexane=2:1), to give 166 g of1-benzyloxycarbonyl-2-(4-fluoro-2-methylphenyl)-4-oxopiperidine as shownin Table 125 below.

Reference Example 3

To 132 g of1-benzyloxycarbonyl-2-(4-fluoro-2-methylphenyl)-4-oxopiperidine wereadded 650 ml of methanol, 84 ml of trimethoxymethane and 2 g of stronglyacidic resin IR-120 (manufactured by Japan Organo Co., Ltd.), and themixture was stirred at room temperature for 3 days. From the reactionmixture was removed insoluble matters by filtration, and the solvent wasremoved by distillation under reduced pressure, to give 146 g of1-benzyloxycarbonyl-2-(4-fluoro-2-methylphenyl)-4,4-dimethoxypiperidineas shown in Table 125 below.

Reference Example 4

In 300 ml of ethanol were added 30 g of1-benzyloxycarbonyl-2-(4-fluoro-2-methylphenyl)-4,4-dimethoxypiperidineand 3.0 g of 10% palladium-carbon, and the mixture was stirred underhydrogen atmosphere at room temperature for 3 hours. From the reactionmixture was removed insoluble matters by filtration, and the solvent wasremoved by distillation under reduced pressure. To the residue was added300 ml of ethyl acetate. Under ice-cooling 20 ml of 4M hydrochloricacid-ethyl acetate solution was slowly added dropwise. The crystals werecollected by filtration and washed with ethyl acetate. After drying, thecrystals were added to a mixture of dichloromethane—an aqueous sodiumcarbonate solution, and the mixture was stirred. After the organic layerwas separated, the aqueous layer was further extracted withdichloromethane. The organic layers were combined and dried over sodiumsulfate, the solvent was removed by distillation under reduced pressure,to give 16.7 g of 2-(4-fluoro-2-methylphenyl)-4,4-dimethoxypiperidine asshown in Table 125 below.

Reference Example 5

To 130 ml of ethyl acetate suspension of 10.1 g of2-(4-fluoro-2-methylphenyl)-4,4-dimethoxypiperidine and 3.18 g ofL-N-acetylvaline was added 35 ml of methanol, and the mixture was heatedto dissolve, and then, cooled down at room temperature. After 3.5 hours,precipitated crystals were collected by filtration, and washed with 20ml of ethyl acetate. The obtained crystals were dried under reducedpressure. Subsequently, 50 ml of chloroform was added thereto, and themixture was washed with 30 ml of a 2M aqueous sodium hydroxide solutionand 30 ml of saturated brine, dried over magnesium sulfate andconcentrated under reduced pressure. To the obtained residue was addedether, and precipitated crystals were further concentrated under reducedpressure, to give 2.94 g of(2R)-2-(4-fluoro-2-methylphenyl)-4,4-dimethoxypiperidine (opticalpurity:97.0% ee) as shown in Table 125 below.

Reference Example 6

In 36 ml of tetrahydrofuran solution of 5.0 g ofN-(3,5-bistrifluoromethylbenzyl)-N-methylamine was added 3.47 g of1,1′-carbonyldiimidazole, and the mixture was stirred at 65° C. for 20minutes. The solvent was removed by distillation under reduced pressureand added thereto was dichloromethane. The whole organic layer waswashed with saturated brine and dried, and the solvent was removed bydistillation. The residue was dissolved in 26 ml of acetonitrile, and4.84 ml of methyl iodide was added thereto and the mixture was stirredat 60° C. for 2 hours. The solvent was removed by distillation underreduced pressure, and the residue was dissolved in 80 ml ofdichloromethane. Under ice-cooling, 5.17 g of2-(4-fluoro-2-methylphenyl)-4,4-dimethoxypiperidine and 3 ml oftriethylamine were added thereto, and the mixture was stirred at roomtemperature for 2 hours. The reaction mixture was poured into water andlayers were separated. The aqueous layer was extracted withdichloromethane. The combined organic layers were washed with saturatedbrine and dried, and the solvent was removed by distillation. Theresidue was purified by silica gel column chromatography (hexane:ethylacetate=4:3), to give 9.7 g of1-{N-(3,5-bistrifluoromethylbenzyl)-N-methyl}aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4,4-dimethoxypiperidineas shown in Table 126 below.

Reference Example 7

In 180 ml of tetrahydrofuran was dissolved 9.7 g of1-{N-(3,5-bistrifluoromethylbenzyl)-N-methyl}aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4,4-dimethoxypiperidine,and under ice-cooling, 70 ml of a 1M aqueous sulfuric acid solution wasadded thereto, and the mixture was stirred at room temperature for anhour. After adjusting pH of the mixture to 8 to 9 by a 1M aqueous sodiumhydroxide solution, tetrahydrofuran was removed by distillation. To theresidue were added water and ethyl acetate, and layers were separated.The aqueous layer was extracted with ethyl acetate. The combined organiclayers were washed with saturated brine and dried. The solvent wasremoved by distillation. To the obtained residue was added diisopropylether, and white crystals were collected by filtration, to give 7.86 gof1-{N-(3,5-bistrifluoromethylbenzyl)-N-methyl}aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-oxopiperidineas shown in Table 126 below.

Reference Example 8

In 60 ml of tetrahydrofuran solution of 3.91 g ofN-{1-(S)-(3,5-bistrifluoromethylphenyl)ethyl}-N-methylamine was added2.34 g of 1,1′-carbonyldiimidazole, and the mixture was stirred at 40°C. overnight. From the reaction mixture the solvent was removed bydistillation, ethyl acetate was added thereto and the whole organiclayer was washed with water and saturated brine, and dried. The solventwas removed by distillation, and the obtained white crystals werecollected by filtration with diisopropyl ether. The obtained whitecrystals were dissolved in 60 ml of acetonitrile and 3.4 ml of methyliodide was added and the mixture was stirred at 60° C. for 2 hours. Thesolvent was removed by distillation under reduced pressure, and theresidue was dissolved in 40 ml of dichloromethane. Under ice-cooling,added thereto were 3.47 g of2-(4-fluoro-2-methylphenyl)-4,4-dimethoxypiperidine and 3.82 ml oftriethylamine and the mixture was stirred at room temperature overnight.The reaction mixture was poured into water and layers were separated.The aqueous layer was extracted with dichloromethane. The combinedorganic layers were washed with water and saturated brine and dried, andthe solvent was removed by distillation under reduced pressure. Theresidue was dissolved in 90 ml of tetrahydrofuran, and underice-cooling, 30 ml of 1M aqueous sulfuric acid solution was addedthereto, and the mixture was stirred at room temperature for 5 hours.After adjusting pH of the mixture to 8 to 9 by a 1M aqueous sodiumhydroxide solution, tetrahydrofuran was removed by distillation. To theresidue were added water and ethyl acetate, and layers were separated.The aqueous layer was extracted with ethyl acetate. The combined organiclayers were washed with water and saturated brine and dried, and thesolvent was removed by distillation under reduced pressure. The residuewas purified by silica gel column chromatography (hexane:ethylacetate=2:1), to give 2.12 g of(2R)-1-[N-{1-(S)-(3,5-bistrifluoromethylphenyl)ethyl}-N-methylaminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-oxopiperidineas shown in Table 126 below.

Reference Examples 9 to 11

The corresponding starting materials were used and treated in the samemanner as in Reference Example 8, to give compounds as shown in Tables126 to 127 below.

Reference Example 12

In 140 ml of ethanol was dissolved 16.7 g of1-benzyloxycarbonyl-2-(4-fluoro-2-methylphenyl)-4-oxopiperidine, andadded thereto were 3.74 g of hydroxylamine hydrochloride and 4.41 g ofsodium acetate, and the mixture was stirred at room temperature for 2hours. Ethanol was removed under reduced pressure. To the residue wereadded water and ethyl acetate, and layers were separated. The aqueouslayer was extracted with ethyl acetate. The combined organic layers werewashed with saturated brine and dried, and the solvent was removed underreduced pressure. The residue was dissolved in 500 ml of methanol, and23.2 g of nickel chloride hexahydrate was added thereto and afterstirring the mixture, 3.7 g of sodium borohydride was slowly added underice-cooling, and the mixture was stirred under ice-cooling for 4 hours.Methanol was removed by distillation under reduced pressure, and to theresidue were added an aqueous ammonia and dichloromethane, and themixture was stirred at room temperature for an hour. The reactionmixture was separated by layers, and the aqueous layer was extractedwith dichloromethane. The combined organic layers were washed withsaturated brine and dried, and the solvent was removed by distillation.The residue was dissolved in 480 ml of dichloromethane, and underice-cooling added thereto were 8.2 ml of triethylamine and 5.1 ml ofpropionyl chloride, and the mixture was stirred under ice-cooling for anhour. The reaction mixture was poured into saturated brine and layerswere separated. The aqueous layer was extracted with dichloromethane.The combined organic layers were washed with saturated brine and dried,and the solvent was removed by distillation under reduced pressure. Theresidue was purified by silica gel column chromatography (hexane:ethylacetate=1:1), to give 6.43 g of (a)trans-1-benzyloxycarbonyl-2-(4-fluoro-2-methylphenyl)-4-propanoylaminopiperidineand 5.65 g of (b)cis-1-benzyloxycarbonyl-2-(4-fluoro-2-methylphenyl)-4-propanoylaminopiperidineas shown in Table 127 below.

Reference Example 13

1-Benzyloxycarbonyl-2-(4-fluoro-2-methylphenyl)-4-oxopiperidine andisobutyroyl chloride were used and treated in the same manner as inReference Example 12, to give (a)trans-1-benzyloxycarbonyl-2-(4-fluoro-2-methylphenyl)-4-isobutanoylaminopiperidineand (b)cis-1-benzyloxycarbonyl-2-(4-fluoro-2-methylphenyl)-4-isobutanoylaminopiperidineas shown in Table 128 below.

Reference Example 14

In 17 ml of ethanol was dissolved 1.73 g oftrans-1-benzyloxycarbonyl-2-(4-fluoro-2-methylphenyl)-4-propanoylaminopiperidine,and added thereto was 280 mg of palladium-carbon (moisture content of50.9%), and the mixture was stirred under hydrogen atmosphere at roomtemperature for 3 hours. The reaction mixture was filtered throughCelite, and ethanol was removed by distillation. The residue waspurified by NH silica gel column chromatography (chloroform:hexane:ethylacetate=5:5:2), to give 772 mg oftrans-2-(4-fluoro-2-methylphenyl)-4-propanoylaminopiperidine as shown inTable 129 below.

Reference Examples 15 to 17

The corresponding starting materials were used and treated in the samemanner as in Reference Example 14, to give compounds as shown in Tables129 to 130 below.

Reference Example 18

In 900 ml of ethanol was dissolved 110 g of1-benzyloxycarbonyl-2-(4-fluoro-2-methylphenyl)-4-oxopiperidine, andadded thereto were 24.8 g of hydroxylamine hydrochloride and 29.3 g ofsodium acetate, and the mixture was stirred at room temperature for 5hours. Ethanol was removed by distillation, and to the residue wereadded water and ethyl acetate. Layers were separated and the aqueouslayer was extracted with ethyl acetate. The combined organic layers werewashed with saturated brine and dried, and the solvent was removed bydistillation under reduced pressure. The residue was dissolved in 2.4 lof methanol, and 92.5 g of nickel chloride hexahydrate was addedthereto. After stirring the mixture, 18.4 g of sodium borohydride wasslowly added under ice-cooling, and the mixture was stirred underice-cooling for 4 hours. Methanol was removed by distillation, and tothe residue were added aqueous ammonia and dichloromethane, and themixture was stirred at room temperature for an hour. The reactionmixture was separated by layers, and the aqueous layer was extractedwith dichloromethane. The combined organic layers were washed withsaturated brine and dried, and the solvent was removed by distillation.The residue was dissolved in 1.2 l of dichloromethane, and underice-cooling added thereto were 45.2 ml of triethylamine, 74.5 ml ofdi-tert-butyldicarbonate, and the mixture was stirred at roomtemperature for an hour. The reaction mixture was poured into saturatedbrine, and the aqueous layer was extracted with dichloromethane. Thecombined organic layers were washed with saturated brine and dried, andthe solvent was removed by distillation under reduced pressure. Theresidue was purified by silica gel column chromatography (hexane:ethylacetate=4:1), to give 36.7 g of (a)trans-1-benzyloxycarbonyl-2-(4-fluoro-2-methylphenyl)-4-tert-butoxycarbonylaminopiperidineand 37.9 g of (b)cis-1-benzyloxycarbonyl-2-(4-fluoro-2-methylphenyl)-4-tert-butoxycarbonylaminopiperidineas shown in Table 131 below.

Reference Example 19

In 350 ml of ethanol was dissolved 37.0 g ofcis-1-benzyloxycarbonyl-2-(4-fluoro-2-methylphenyl)-4-tert-butoxycarbonylaminopiperidine,and 5.5 g of palladium-carbon (moisture content of 50.9%) was addedthereto, and the mixture was stirred under hydrogen atmosphere at roomtemperature for 2 hours. The reaction mixture was filtered throughCelite, and ethanol was removed by distillation, to give 25.8 g ofcis-2-(4-fluoro-2-methylphenyl)-4-tert-butoxycarbonylaminopiperidine asshown in Table 132 below.

Reference Example 20

To 1.34 g of 3-hydroxyl-2-hydroxymethyl-2-methylpropionic acid and 13 mlof acetonedimethylacetal was added 95 mg of p-toluenesulfonic acidmonohydrate at room temperature, and the mixture was stirred for 6hours. Further added thereto was 95 mg of p-toluenesulfonic acidmonohydrate, and the mixture was stirred overnight. The solution wasconcentrated and poured into water and extracted. The aqueous layer wasextracted with chloroform. The combined organic layers were washed withsaturated brine, dried, and concentrated. The residue was purified bysilica gel column chromatography (chloroform:methanol=19:1), to give 333mg of 2,2,5-trimethyl-(1,3]dioxolane-5-carboxylic acid as shown in Table132 below.

Reference Example 21

In 400 ml of tetrahydrofuran was dissolved 31.5 g of2-chloroisonicotinic acid, and 32.5 g of 1,1′-carbonyldiimidazole wasadded thereto. The mixture was stirred under ice-cooling for an hour. Tothe solution was added 50 ml of ethanol, and the mixture was stirred atroom temperature for 2 hours. The solution was concentrated, andextracted by adding ethyl acetate and water. The organic layer was driedover magnesium sulfate, and the residue was vacuum dried, to give 35.6 gof ethyl 2-chloroisonicotinate as shown in Table 132 below.

Reference Example 22

In a mixed solvent of 250 ml of toluene and 50 ml of ethanol weredissolved 20 g of ethyl 2-chloroisonicotinate and 20 g of2-methyl-4-fluorophenylboronic acid, and 5.8 g of palladiumtetrakistriphenylphosphine and 250 ml of a 2M aqueous sodium carbonatesolution, and the mixture was stirred at 50 to 70° C. for 2 hours. Thesolution was cooled down to room temperature and extracted by addingethyl acetate and water. The organic layer was further washed withwater, and dried over magnesium sulfate and concentrated. The residuewas purified by silica gel column chromatography (hexane:ethylacetate=6:1), to give 24.8 g of4-ethoxycarbonyl-2-(4-fluoro-2-methylphenyl)pyridine as shown in Table132 below.

Reference Example 23

In 200 ml of ethanol were dissolved 5.2 g of4-ethoxycarbonyl-2-(4-fluoro-2-methylphenyl)pyridine and 1.5 g ofplatinum oxide, and 15 ml of concentrated hydrochloric acid was added tothe solution. The mixture was stirred under hydrogen atmosphere at roomtemperature for 5 hours. Added thereto was 200 ml of water and themixture was stirred for 30 minutes, and then, insoluble matters wereremoved by filtration through Celite. The insoluble matters were washedwith ethanol and the filtrate and the liquid used for washing werecombined and concentrated. To the residue were added ethyl acetate and asaturated aqueous sodium hydrogen carbonate solution. After confirmingthat the aqueous solution was sufficiently alkaline, then extraction wascarried out. The aqueous layer was extracted with ethyl acetate for 3times, and the combined organic layers were dried over sodium sulfateand concentrated, to give 3.6 g of2,4-cis-4-ethoxycarbonyl-2-(4-fluoro-2-methylphenyl)piperidine as shownin Table 132 below.

Reference Example 24

(1) In a mixture of 50 ml of ethyl acetate and 50 ml of diethyletherwere dissolved under heating 7.4 g of2,4-cis-4-ethoxycarbonyl-2-(4-fluoro-2-methylphenyl)piperidine and 4.0 gof N-p-toluenesulfonyl-D-phenylalanine. The solvent was concentrated byheating, 30 ml of diisopropyl ether was added thereto and the mixturewas stirred. Precipitated crystals were removed and mother liquor waswashed with a concentrated aqueous ammonia solution, dried andconcentrated under reduced pressure. To the residue was added 4.0 g ofN-p-toluenesulfonyl-L-phenylalanine, and 50 ml of ethyl acetate and 30ml of diisopropyl ether were added thereto and dissolved by heating, themixture was stirred at room temperature for 16 hours. Precipitatedcrystals were collected by filtration, washed with diisopropyl ether,and dried, to give 4.0 g of N-p-toluenesulfonyl-L-phenylalanine salt of(2R,4S)-4-ethoxycarbonyl-2-(4-fluoro-2-methylphenyl)-4-piperidine.

(2) The compound of the above (1) was dissolved in an aqueous ammoniasolution, and after confirming that the solution was sufficiently basic,it was extracted with chloroform twice. The combined organic layers weredried and concentrated under reduced pressure, to give 2.6 g of(2R,4S)-4-ethoxycarbonyl-2-(4-fluoro-2-methylphenyl)-4-piperidine(optical purity: 96% ee) as shown in Table 133 below.

Reference Example 25

(1) In 50 ml of N,N-dimethylformamide was dissolved 7.5 g of3-aminopropanol, and 16 g of tert-butyldimethylsilyl chloride and 6.8 gof imidazole were added thereto, and the mixture was stirred at roomtemperature for 16 hours. To the reaction mixture was added 11 g ofcitric acid and after stirring the mixture at room temperature for anhour, the mixture was concentrated under reduced pressure. To theresidue were added a 2M aqueous sodium hydroxide solution and diethylether and layers were separated. The organic layer was dried andconcentrated under reduced pressure. The residue and 12.1 g of3,5-bistrifluoromethylbenzaldehyde were dissolved in 300 ml ofdichloromethane and 21.2 g of sodium triacetoxy borohydride and 2.9 mlof acetic acid were added and the mixture was stirred at roomtemperature for 3 hours. To the reaction mixture was added a 2M aqueoussodium carbonate solution. The mixture was stirred for 30 minutes, andextracted with chloroform twice. The combined organic layers were dried,concentrated under reduced pressure, and purified by silica gel columnchromatography(hexane:ethyl acetate=4:1), to give 20 g of3-tert-butyldimethylsiloxypropyl-3,5-bistrifluoromethylbenzylamine.

(2) 12.5 g of the compound of the above (1) and the compound ofReference Example 5 were used and treated in the same manner as inReference Example 6, to give 19 g of(2R)-1-{N-(3,5-bistrifluoromethylbenzyl)-N-(3-tert-butyldimethylsiloxypropyl)}aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4,4-dimethoxypiperidine.

(3) 19.0 g of the compound of the above (2) was used and treated in thesame manner as in Reference Example 7, to give 19 g of(2R)-1-{N-(3,5-bistrifluoromethylbenzyl)-N-(3-hydroxypropyl)}aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-oxopiperidineas shown in Table 133 below.

Reference Example 26

(1) In 40 ml of dichloromethane was dissolved 4.8 g of the compound ofReference Example 5, and 4.4 g of di-tert-butyldicarbonate was addedthereto and the mixture was stirred at room temperature for 16 hours.The reaction mixture was concentrated under reduced pressure. Theresidue was dissolved in 100 ml of acetone, and 200 mg of an acidicresin (IR-120) was added thereto and the mixture was stirred at roomtemperature for 3 days. After removing the resine from the reactionmixture, the mixture was concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography (hexane:ethylacetate=4:1), to give 3.9 g of(R)-1-tert-butoxycarbonyl-2-(4-fluoro-2-methylphenyl)-4-oxopiperidine.

(2) In 20 ml of ethanol was dissolved 3.9 g of the compound of the above(1), added thereto was 400 mg of sodium borohydride at −20° C., and themixture was stirred for an hour. To the reaction mixture was added anaqueous ammonium chloride solution, and ethanol was removed bydistillation. To the residue were added ethyl acetate and water andlayers were separated, and further washed with water. The organic layerwas dried and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (hexane:ethyl acetate=4:1),to give 3.1 g of(2R,4S)-1-tert-butoxycarbonyl-2-(4-fluoro-2-methylphenyl)-4-hydroxypiperidine.

(3) 3.1 g of the compound of the above (2) and the correspondingstarting material were used and treated in the same manner as in Example209, to give 2.3 g of(2R,4S)-1-tert-butoxycarbonyl-2-(4-fluoro-2-methylphenyl)-4-(2-hydroxyethylaminocarbonyloxy)piperidine.

(4) In 20 ml of a 4M hydrochloric acid-ethyl acetate solution wasdissolved 2.3 g of the compound of the above (3), and the solution wasstirred at room temperature for an hour. The reaction mixture wasconcentrated under reduced pressure. The residue was dried, to give 1.5g of(2R,4S)-2-(4-fluoro-2-methylphenyl)-4-(2-acetoxyethylaminocarbonyloxy)piperidinehydrochloride.

(5) In 25 ml of a 1M aqueous sodium hydroxide solution was dissolved 1.5g of the compound of the above (4), and the solution was extracted withchloroform twice. The combined organic layers were dried andconcentrated under reduced pressure. The residue was dried, to give 1.5g of(2R,4S)-2-(4-fluoro-2-methylphenyl)-4-(2-hydroxyethylaminocarbonyloxy)piperidineas shown in Table 133 below.

Reference Example 27

In 250 ml of acetonitrile was dissolved 4.8 g of3,5-bistrifluoromethylbenzaldehyde, added thereto were 6.6 g oftrimethylsulfonium iodide, 3.2 g of ground potassium hydroxide and 0.5ml of water, and the mixture was stirred at a temperature of 65° C. to70° C. for 16 hours, in the presence of an alumina ball. After thereaction was completed, insoluble matters were removed, and ethylacetate and water were added to the filtrate and layers were separated.The organic layer was washed, dried and concentrated under reducedpressure. To the residue was added 50 ml of a 40% methylamine-methanolsolution, and the mixture was stirred at room temperature for 16 hours.The reaction mixture was concentrated under reduced pressure. Theresidue was purified by NH silica gel column chromatography(hexane:ethyl acetate=1:2), to give 1.23 g of1-(3,5-bistrifluoromethylphenyl)-2-hydroxyethylamine as shown in Table133 below.

Reference Example 28

(1) In 43 ml of dichloromethane were dissolved 2.45 g of3,5-bistrifluoromethylbenzaldehyde, 835 mg of 2-methoxyethylamine and687 μl of acetic acid, added thereto was 3.12 g of sodium triacetoxyborohydride, and the mixture was stirred at room temperature for an hourunder nitrogen atmosphere. The reaction mixture was washed with a 0.5Maqueous sodium hydroxide solution, dried over magnesium sulfate, andconcentrated under reduced pressure. The residue was purified by NHsilica gel column chromatography (hexane:ethyl acetate=19:1→9:1), togive 2.76 g of 3,5-bistrifluoromethylbenzyl-2-methoxyethylamine.

MS(m/z): 302 [M⁺+1]⁺

(2) In a mixed solution of 37 ml of toluene and 4 ml of methylenechloride was dissolved 2.76 g of3,5-bistrifluoromethylbenzyl-2-methoxyethylamine, added thereto was 1.78g of 1,1′-carbonyldiimidazole, and the mixture was stirred at 60° C. for3 hours. To the reaction mixture was added distilled water, andextracted with chloroform. The organic layer was dried over magnesiumsulfate, dried and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography(chloroform:acetone=9:1→2:1), to give 3.45 g of imidazole-1-carboxylicacid 3,5-bistrifluoromethylbenzyl-2-methoxyethylamide as shown in Table133 below.

Reference Example 29

(1) In 15 ml of N,N-dimethylformamide were dissolved 3.94 g of2-bromo-5-fluorophenol and 1.62 ml of methyl iodide, slowly addedthereto was 5.08 g of potassium carbonate under ice-cooling. The mixturewas stirred at room temperature for 3 hours. After insoluble matterswere removed by filtration, distilled water was added to the filtrate,and the mixture was extracted with diethyl ether and washed withsaturated brine. The organic layer was dried over magnesium sulfate andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography-(hexane:ethyl acetate=19:1→9:1), to give 4.10g of 1-bromo4-fluoro-2-methoxybenzene.

MS(m/z): 204/206 (M⁺+1)_(o)

(2) To 7 ml of tetrahydrofuran were added 486 mg of magnesium and traceof iodine, and dropped thereto was a solution of 4.10 g of the compoundof the above (1) in 16 ml of tetrahydrofuran, to prepare Grignardreagent. To the solution, a solution of 1.96 g of 4-methoxypyridine in 7ml of tetrahydrofuran was added dropwise under nitrogen atmosphere at−60° C. or below. Subsequently, a solution of 3.75 g of benzylchloroformate in 18 ml of tetrahydrofuran was added dropwise, and themixture was stirred for 3 hours. The temperature of the mixture wasraised to room temperature, and 40 ml of a 5% aqueous citric acidsolution was added thereto. The mixture was extracted with ethyl acetateand washed with saturated brine. The organic layer was dried andconcentrated. The residue was purified by silica gel columnchromatography (hexane:ethyl acetate=2:1→1:2), to give 3.15 g of1-benzyloxycarbonyl-2-(4-fluoro-2-methoxyphenyl)-4-oxo-3,4-dihydro-2H-pyridine.

MS(m/z): 356 [M⁺+1]

(3) In a mixed solution of 79 ml of ethanol and 6 ml of tetrahydrofuranwas dissolved 3.15 g of the compound of the above (2), and added theretowas 706 mg of sodium borohydride and the mixture was stirred at roomtemperature for 6 hours. The reaction mixture was concentrated anddistilled water was added to the residue. The mixture was extracted withchloroform, and the organic layer was dried and concentrated underreduced pressure. The residue was purified by silica gel columnchromatography (chloroform:acetone=19:1→9:1), to give 1.62 g of1-benzyloxycarbonyl-2-(4-fluoro-2-methoxyphenyl)-4-hydroxypiperidine.

MS(m/z): 360 [M⁺+1]

(4) In 20 ml of toluene was dissolved 1.62 g of the compound of theabove (3), added thereto was 876 mg of 1,1′-carbonyldiimidazole and themixture was stirred at 60° C. for an hour. Added thereto was 1.09 ml ofethanolamine, and the mixture was stirred at 60° C. for 6 hours. To thereaction mixture was added distilled water and the mixture was extractedwith chloroform. The organic layer was dried and concentrated. Theresidue was purified by silica gel column chromatography(chloroform:acetone=4:1→1:1), to give 1.81 g of1-benzyloxycarbonyl-2-(4-fluoro-2-methoxyphenyl)-4-(2-hydroxyethylaminocarbonyloxy)piperidine.

MS(m/z): 447 [M⁺+1]

(5) In 20 ml of methanol was dissolved 1.81 g of the compound of theabove (4), and added thereto was 90 mg of 10% palladium-carbon, and themixture was stirred at room temperature for an hour under hydrogenatmosphere. After insoluble matters were removed by filtration, thefiltrate was concentrated. To the residue was added diethyl ether andprecipitates were collected by filtration, to give 1.30 g of 2-(4-fluoro2-methoxyphenyl)-4-(2-hydroxyethylaminocarbonyloxy)piperidine as shownin Table 134 below.

Reference Example 30

(1) In 40 ml of tetrahydrofuran was dissolved 5.46 g of4-methoxypyridine, and added dropwise thereto was 55 ml of a 1Mphenylmagnesiumbromide-tetrahydrofuran solution under nitrogenatmosphere at −60° C. of below. Subsequently, added dropwise thereto wasa solution of 10.24 g of benzyl chloroformate in 50 ml oftetrahydrofuran, and the mixture was stirred for 3 hours. Thetemperature of the mixture was raised to room temperature, and 120 ml ofa 5% aqueous citric acid solution was added thereto. The mixture wasextracted with ethyl acetate and washed with saturated brine. Theorganic layer was dried and concentrated. To the residue was addeddiisopropyl ether and the precipitates were collected by filtration, togive 8.51 g of1-benzyloxycarbonyl-4-oxo-2-phenyl-3,4-dihydro-2H-pyridine.

MS(m/z): 308 [M⁺+1]

(2) In 260 ml of acetic acid was dissolved 8.48 g of the compound of theabove (1), added thereto was 3.61 g of zinc powder, and the mixture wasstirred at room temperature for 18 hours. Subsequently, 1.8 g of zincpowder was added and after stirring the mixture at room temperature for6 hours, 1.8 g of zinc powder was further added thereto and the mixturewas stirred at 50° C. for 3 days. After insoluble matters were removedby filtration, the filtrate was concentrated under reduced pressure. Theresidue was extracted with ethyl acetate, and washed with a saturatedaqueous sodium hydrogen carbonate solution and saturated brine. Theorganic layer was dried and concentrated, to give 8.54 g of1-benzyloxycarbonyl-4-oxo-2-phenylpiperidine.

MS(m/z): 310 [M⁺+1]

(3) In 15 ml of tetrahydrofuran was dissolved 619 mg of the compound ofthe above (2), and added dropwise thereto was 4 ml of a 1Mdiisobutylalminiun hydride solution in toluene under nitrogen atmosphereat −60° C. or below. The mixture was stirred for 10 minutes. To thereaction mixture was added 667 μl of a 6M aqueous hydrochloric acidsolution, and the mixture was concentrated. To the residue was addeddistilled water and the mixture was extracted with ethyl acetate. Theorganic layer was washed with saturated brine, dried and concentratedunder reduced pressure. The residue was purified by silica gel columnchromatography (hexane:ethyl acetate=2:1→1:1), to give 553 mg of1-benzyloxycarbonyl-4-hydroxy-2-phenylpiperidine.

MS(m/z): 312 [M⁺+1]

(4) In a mixed solution of 14 ml of toluene and 1.6 ml ofdichloromethane was added 511 mg of the compound of the above (3), andadded thereto was 319 mg of 1,1′-carbonyldiimidazole, and the mixturewas stirred at 60° C. for 2 hours. Added thereto was 396 μl ofethanolamine, and the mixture was stirred at 60° C. for 3 hours. To thereaction mixture was added distilled water and the mixture was extractedwith chloroform. The organic layer was dried and concentrated. Theresidue was purified by silica gel columnchromatography(chloroform:acetone=9:1→2:1), to give 462 mg of1-benzyloxycarbonyl-4-(2-hydroxyethylaminocarbonyloxy)-2-phenylpiperidine.

MS(m/z): 399 [M⁺+1]

(5) In 10 ml of methanol was dissolved 430 mg of the compound of theabove (4), and added thereto was 30 mg of 10% palladium-carbon, and themixture was stirred at room temperature for 5 days under hydrogenatmosphere. Insoluble matters were removed by filtration and thefiltrate was concentrated, to give 348 mg of4-(2-hydroxyethylaminocarboxyoxy)-2-phenylpiperidine as shown in Table134 below.

Reference Example 31

(1) In 47 ml of ethanol was dissolved 2.61 g of3,5-bistrifluoromethylacetophenone, added thereto was 478 mg of sodiumborohydride, and the mixture was stirred at room temperature for 30minutes. To the reaction mixture was added a saturated aqueous ammoniumchloride solution and the mixture was concentrated. The residue wasextracted with ethyl acetate and washed with saturated brine. Theorganic layer was dried and concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography (hexane:ethylacetate=9:1→4:1), to give 2.51 g of1-(3,5-bistrifluoromethylphenyl)-ethanol.

MS(m/z): 258 [M⁺+1]

(2) In a mixed solution of 40 ml of toluene and 4 ml of acetonitrile wasdissolved 2.49 g of the compound of the above (1), added thereto was1.72 g of 1,1′-carbonyldiimidazole, and the mixture was stirred at roomtemperature for 3 hours. To the reaction mixture was added water and themixture was extracted with ethyl acetate and washed with saturatedbrine. The organic layer was dried and concentrated under reducedpressure, to give 3.40 g of 1-(3,5-bistrifluoromethylphenyl)ethylimidazole-1-carboxylate as shown in Table 134 below.

Reference Example 32

To 1.74 g of magnesium and 40 ml of tetrahydrofuran was added trace ofiodine, and under nitrogen atmosphere and at room temperature, 10.4 g of2-bromo-5-fluorotoluene was added dropwise spending 40 minutes. Thereaction mixture was refluxed under heating for an hour, to prepareGrignard reagent solution. To the prepared Grignard reagent solution wasadded dropwise 5.46 g of 4-methoxypyridine spending 20 minutes, at −40°C. under nitrogen atmosphere. After completion of dropwise addition, themixture was stirred at a temperature from −40° C. to −30° C. for 30minutes. Subsequently, the reaction mixture was cooled down to −40° C.,and while keeping the temperature at −40° C. or below, added dropwisethereto was a solution of 12 g of di-tert-butyldicarbonate in 20 ml oftetrahydrofuran. After completion of dropwise addition, the temperatureof the reaction mixture was slowly raised. At −15° C., ice was addedthereto and the mixture was stirred for 20 minutes. Further addedthereto was an aqueous citric acid solution and the mixture was stirredat room temperature for 40 minutes. Tetrahydrofuran was removed bydistillation and to the resultant residue was added ethyl acetate, andextracted twice. The combined organic layers were washed with saturatedbrine, dried and concentrated under reduced pressure. To the residue wasadded diisopropyl ether, and the obtained crystals were collected byfiltration with diisopropyl ether, to give 11.9 g of1-tert-butoxycarbonyl-2-(4-fluoro-2-methylphenyl)-4-oxo-3,4-dihydro-2H-pyridineas shown in Table 134 below.

Reference Example 33

To 6.0 ml of ethanol were added 916 mg of1-tert-butoxycarbonyl-2-(4-fluoro-2-methylphenyl)-4-oxo-3,4-dihydro-2H-pyridineand 110 mg of 10% palladium-carbon (moisture content of 50.5%), and themixture was stirred at room temperature for 12 hours under hydrogenatmosphere. After insoluble matters were removed by filtration, thesolvent was removed by distillation. The residue was dissolved in 15 mlof toluene and the solution was cooled down to −78° C. To the solutionwas slowly added dropwise 1.8 ml of butyl lithium aluminum hydride (a65% by weight toluene solution) under nitrogen atmosphere. Aftercompletion of dropwise addition, the mixture was stirred at atemperature from −78° C. to −60° C. for an hour. To the reaction mixturewas added a 1M aqueous sodium hydroxide solution, and the mixture wasstirred for 10 minutes. Formed precipitates were separated by filtrationthrough Celite, and extracted with ethyl acetate twice. The organiclayers were combined and washed with saturated aqueous ammonia andsaturated brine. The organic layer was dried and concentrated underreduced pressure. After adding 7.5 ml of ethyl acetate to the residue,slowly added dropwise thereto was 7.5 ml of 4M hydrochloric acid-ethylacetate solution under ice-cooling. Crystals were collected byfiltration and washed with ethyl acetate. After drying, the crystalswere added to a mixture of ethyl acetate-a 1M aqueous sodium hydroxidesolution, and stirred. The organic layer was separated and the aqueouslayer was extracted with ethyl acetate for 3 times. The organic layerswere combined and dried over sodium sulfate. The solvent was removed bydistillation under reduced pressure, to give 471 mg of2-(4-fluoro-2-methyl)phenyl-4-hydroxypiperidine as shown in Table 134below.

Reference Example 34

In 3.0 ml of dichloromethane was dissolved 831 ml of triphosgene, andadded dropwise thereto were a solution of 1.08 g ofN-(3,5-bistrifluoromethylbenzyl)-N-methylamine and 1.76 ml oftriethylamine in 5.0 ml of dichloromethane, spending 10 minutes, undernitrogen atmosphere under ice-cooling. The reaction mixture was stirredat 0° C. to 5° C. for 30 minutes. The solvent was removed bydistillation, and the residue was dried. To the residue were added waterand dichloromethane and the mixture was extracted twice withdichloromethane. The organic layers were combined and washed withsaturated brine, and dried. Then, the solvent was removed bydistillation. The residue was purified by silica gel columnchromatography (hexane→hexane:ethyl acetate=10:1), to give 760 mg ofN-(3,5-bistrifluoromethylbenzyl)-N-methylaminocarbonyl chloride as shownin Table 134 below.

Reference Example 35

In 20 ml of methanol was dissolved 24.5 g of3,5-bistrifluoromethylbenzaldehyde, and under ice-cooling, added theretowas 60 ml of ethylamine (a 2M tetrahydrofuran solution). Subsequently,4.38 g of sodium borohydride was slowly added thereto, and the mixturewas stirred at room temperature for 3 hours. To the reaction mixture wasadded distilled water and concentrated under reduced pressure. Theresidue was extracted with dichloromethane, and the organic layer wasdried and concentrated under reduced pressure. The residue was purifiedby silica gel column chromatography (hexane:ethylacetate=4:1→chloroform:methanol=9:1), to give 6.35 g ofN-(3,5-bistrifluoromethylbenzyl)-N-ethylamine as shown in Table 135below.

Reference Example 36

(1) To 20 ml of tetrahydrofuran were added 1.34 g of magnesium and traceof iodine, and added dropwise thereto was a solution of 9.50 g of2-bromotoluene in 45 ml of tetrahydrofuran, to prepare Grignard reagent.To the Grignard reagent was added dropwise a solution of 5.46 g of4-methoxypyridine in 20 ml of tetrahydrofuran under nitrogen atmosphereat −60° C. or below. Subsequently, a solution of 10.24 g of chlorobenzylformate in 50 ml of tetrahydrofuran was added dropwise thereto at −40°C. and the mixture was stirred for 3 hours. The temperature of themixture was raised to room temperature and added thereto was 120 ml of a5% aqueous citric acid solution. The mixture was extracted with ethylacetate and washed with saturated brine. The organic layer was dried andconcentrated under reduced pressure. The residue was crystallized withdiisopropyl ether, and the crystals were collected by filtration, togive 11.15 g of1-benzyloxycarbonyl-2-(2-methylphenyl)-4-oxo-3,4-dihydro-2H-pyridine.

MS(m/z): 322 (M⁺+1]

(2) In a mixed solution of 125 ml of ethanol and 35 ml oftetrahydrofuran was dissolved 11.15 g of1-benzyloxycarbonyl-2-(2-methylphenyl)-4-oxo-3,4-dihydro-2H-pyridine,added thereto was 2.76 g of sodium borohydride, and the mixture wasstirred at room temperature for a day. Further added thereto was 1.38 gof sodium borohydride, and the mixture was stirred at room temperaturefor a day. The reaction mixture was concentrated under reduced pressureand to the residue was added distilled water. The mixture was extractedwith chloroform, and the organic layer was dried and concentrated underreduced pressure. The residue was purified by silica gel columnchromatography (chloroform:acetone=49:1→9:1), to give 6.18 g of1-benzyloxycarbonyl-4-hydroxy-2-(2-methylphenyl piperidine.

MS(m/z): 326 [M⁺+1]

(3) In 21 ml of toluene was dissolved 1.63 g of1-benzyloxycarbonyl-4-hydroxy-2-(2-methylphenyl)piperidine, addedthereto was 973 mg of 1,1′-carbonyldiimidazole, and the mixture wasstirred at 60° C. for an hour. To the solution was added 1.21 ml ofethanolamine, and the mixture was stirred at 60° C. for 6 hours. To thereaction mixture was added distilled water, and extracted withchloroform. The organic layer was dried and concentrated under reducedpressure. The residue was purified by silica gel column chromatography(chloroform:acetone=9:1→chloroform:methanol=19:1), to give 1.34 g of1-benzyloxycarbonyl-4-(2-hydroxyethylaminocarbonyloxy)-2-(2-methylphenyl)piperidine.

MS(m/z): 413 [M⁺+1]

(4) In 30 ml of methanol was dissolved 1.33 g of1-benzyloxycarbonyl-4-(2-hydroxyethylaminocarbonyloxy)-2-(2-methylphenyl)piperidine,and added thereto was 70 mg of 10% palladium-carbon, and the mixture wasstirred at room temperature for 14 hours under hydrogen atmosphere.After insoluble matters were removed by filtration, the filtrate wasconcentrated, to give 880 mg of4-(2-hydroxyethylaminocarbonyloxy)-2-(2-methylphenyl)piperidine as shownin Table 135 below.

Reference Example 37

(1) 25 g of 4-fluoro-1-bromobenzene was used and treated in the samemanner as in Reference Example 1, to give 22.3 g of1-benzyloxycarbonyl-2-(4-fluorophenyl)-4-oxo-3,4-dihydro-2H-pyridine.

(2) In 400 ml of ethanol was dissolved 20 g of the compound of the above(1), and added thereto was 7.6 g of sodium borohydride, and the mixturewas stirred at −20° C. for 2 hours. After reaction was completed, slowlyadded thereto was an aqueous citric acid solution until no foam wasgenerated. The solvent was removed by distillation under reducedpressure, and layers were separated with addition of water andchloroform. The aqueous layer was further extracted with chloroform, andthe combined organic layers were dried and concentrated under reducedpressure. The residue was purified by silica gel column chromatography(chloroform:ethyl acetate=10:1), to give 6.3 g of a mixture of (a)(2R,4S)-1-benzyloxycarbonyl-2-(4-fluorophenyl)-4-hydroxypiperidine and(b) (2S,4R)-1-benzyloxycarbonyl-2-(4-fluorophenyl)-4-hydroxypiperidine.

(3) 6.2 g of the compound of the above (2) was used and treated in thesame manner as in Example 209, to give 7.3 g of a mixture of (a)(2R,4S)-1-benzyloxycarbonyl-2-(4-fluorophenyl)-4-(2-hydroxyethylaminocarbonyloxy)piperidineand (b)(2S,4R)-1-benzyloxycarbonyl-2-(4-fluorophenyl)-4-(2-hydroxyethylaminocarbonyloxy)piperidine.

(4) 6.3 g of the compound of the above (3) was used and treated in thesame manner as in Reference Example 4, to give 2.6 g of a mixture of (a)(2R,4S)-2-(4-fluorophenyl)-4-(2-hydroxyethylaminocarbonyloxy)piperidineand (b)(2S,4R)-2-(4-fluorophenyl)-4-(2-hydroxyethylaminocarbonyloxy)piperidineas shown in Table 135 below.

Reference Example 38

In 5 ml of methanol was dissolved 0.639 g of N-tosyl-D-phenylalanine,and the solution was warmed up to 59° C. and then added dropwise theretowas 1.3 ml of methanol solution containing 0.418 g of2-(4-fluro-2-methyl)phenyl-4-hydroxypiperidine. After the crystals wereformed in 20 minutes from the beginning of the crystallization, theother methanol solution in2-(4-fluro-2-methyl)phenyl-4-hydroxypiperidine was added dropwise to themixture in the period of 5 minutes. The mixture was cooled down from 59°C. to 30° C. in one hour, and then the crystals were formed for 1.5hours. The obtained crystal was removed by filtration and washed bycooled-methanol, and dried by air at 60° C. for one night to give 0.325g of (2R,4S)-2-(4-fluro-2-methyl)phenyl-4-hydroxypiperidineN-tosyl-D-phenylalanine salt. The obtained salt was added 0.62 ml of a 2M aqueous hydrogen chloride solution, the mixture was extracted withethyl acetate. The water layer was added 0.3 ml of a 5 M aqueous sodiumhydroxide and then extracted with ethyl acetate for four times. Theorganic layer was dried, concentrated under reduced pressure, to give0.129 g of (2R,4S)-2-(4-fluro-2-methyl)phenyl-4-hydroxypiperidine asshown in Table 136 below.

Reference Example 39

In 40 ml of dichloromethane was dissolved 2.72 g of2-methoxy-5-(5-trifluoromethyltetrazole-1-yl)benzaldehyde, and addedthereto was 2.5 ml of 8 M methylamine in ethanol solution, 0.572 ml ofacetic acid and 3.12 g of triacetoxy sodium borohydride, the mixture wasstirred at room temperature for 6 hours. The reaction mixture was washedwith saturated aqueous sodium hydrocarbonate solution, and the organiclayers were dried and concentrate. The residue was purified by silicagel column chromatography (chloroform:methanol=49:1 to 4:1), to give 2.2g ofN-{2-methoxy-5-(5-trifluromethyltetrazole-1-yl)benzyl}-N-methylamine asshown in Table 136 below. TABLE 1 Ex- ample No. Structural Formula MS 1(1)

493 (M⁺ + 1) 1 (2) (a)

493 (M⁺ + 1) 1 (2) (b)

493 (M⁺ + 1)

TABLE 2 Ex- ample No. Structural Formula MS 2 (a)

507 (M⁺ + 1) 2 (b)

507 (M⁺ + 1) 3 (a)

493 (M⁺ + 1) 3 (b)

493 (M⁺ + 1)

TABLE 3 Ex- ample No. Structural Formula MS 4 (a)

507 (M⁺ +1) 4 (b)

507 (M⁺ +1)

TABLE 4

Example No. R¹ n MS 5

0 584 (M⁺ + 1) 6

1 564 (M⁺ + 1) 7

1 604 (M⁺ + 1)

TABLE 5 Ex- am- ple No. Structural Formula MS 8 (a)

560 (M⁺ +1) 8 (b)

560 (M⁺ +1)

TABLE 6 Ex- ample No. Structural Formula MS 9 (a)

546 (M⁺ +1) 9 (b)

546 (M⁺ +1)

TABLE 7 Ex- ample No. Structural Formula MS 10 (a)

520 (M⁺+1) 10 (b)

520 (M⁺+1)

TABLE 8 Ex- am- ple No. Structural Formula MS 11 (a)

548 (M⁺ +1) 11 (b)

548 (M⁺ +1)

TABLE 9 Example No. Structural Formula MS 12 (a)

643 (M⁺ + 1) 12 (b)

643 (M⁺ + 1)

TABLE 10 Example No. Structural Formula MS 13 (a)

574 (M⁺ + 1) 13 (b)

574 (M⁺ + 1)

TABLE 11 Ex- am- ple No. Structural Formula MS 14 (a)

562 (M⁺ +1) 14 (b)

562 (M⁺ +1)

TABLE 12

Example No. R¹ MS 15 (a)

560 (M⁺ + 1) 15 (b)

560 (M⁺ + 1) 16 (a)

546 (M⁺ + 1) 16 (b)

546 (M⁺ + 1) 17 (a)

562 (M⁺ + 1) 17 (b)

562 (M⁺ + 1) 18 (a)

520 (M⁺ + 1) 18 (b)

520 (M⁺ + 1) 19 (a)

548 (M⁺ + 1) 19 (b)

548 (M⁺ + 1)

TABLE 13

Example No. R¹ MS 20 (a)

574 (M⁺ + 1) 20 (b)

574 (M⁺ + 1) 21 (a)

560 (M⁺ + 1) 21 (b)

560 (M⁺ + 1) 22 (a)

576 (M⁺ + 1) 22 (b)

576 (M⁺ + 1)

TABLE 14

Example No. R¹ MS 23 (a)

534 (M⁺ + 1) 23 (b)

534 (M⁺ + 1) 24 (a)

562 (M⁺ + 1) 24 (b)

562 (M⁺ + 1) 25 (a)

588 (M⁺ + 1) 25 (b)

588 (M⁺ + 1)

TABLE 15

Example No. R¹ MS 26 (a)

574 (M⁺ + 1) 26 (b)

574 (M⁺ + 1) 27 (a)

560 (M⁺ + 1) 27 (b)

560 (M⁺ + 1) 28 (a)

576 (M⁺ + 1) 28 (b)

476 (M⁺ + 1) 29 (a)

534 (M⁺ + 1) 29 (b)

534 (M⁺ + 1) 30 (a)

576 (M⁺ + 1) 30 (b)

576 (M⁺ + 1)

TABLE 16

Example No. R¹ n MS 31

1 534 (M⁺ + 1) 32

2 605 (M⁺ + 1) 33

1 564 (M⁺ + 1) 34

1 559 (M⁺ + 1) 35

2 577 (M⁺ + 1) 36

1 506 (M⁺ + 1) 37

1 562 (M⁺ + 1) 38

2 611 (M⁺ + 1)

TABLE 17

Example No. R¹ MS 39

578 (M⁺ + 1) 40

604 (M⁺ + 1) 41

578 (M⁺ + 1) 42

605 (M⁺ + 1)

TABLE 18

Example No. R¹ MS 43 (a)

574 (M⁺ + 1) 43 (b)

574 (M⁺ + 1) 44 (a)

560 (M⁺ + 1) 44 (b)

560 (M⁺ + 1)

TABLE 19 Ex- ample No. Structural Formula MS 45

492 (M⁺ + 1) 46

492 (M⁺ + 1)

TABLE 20 Example No. Structural Formula MS 47 (a)

592 (M⁺ + 1) 47 (b)

592 (M⁺ + 1)

TABLE 21 Ex- ample No. Structural Formula MS 48

492 (M⁺ + 1) 49

492 (M⁺ + 1)

TABLE 22 Example No. Structural Formula MS 50 (a)

548 (M⁺ + 1) 50 (b)

548 (M⁺ + 1)

TABLE 23 Example No. Structural Formula MS 51 (a)

562 (M⁺ + 1) 51 (b)

562 (M⁺ + 1)

TABLE 24 Example No. Structural Formula MS 52 (a)

576 (M⁺ + 1) 52 (b)

576 (M⁺ + 1)

TABLE 25 Example No. Structural Formula MS 53 (a)

550 (M⁺ + 1) 53 (b)

550 (M⁺ + 1)

TABLE 26 Example No. Structural Formula MS 54 (a)

564 (M⁺ + 1) 54 (b)

564 (M⁺ + 1)

TABLE 27 Example No. Structural Formula MS 55 (a)

596 (M⁺ + 1) 55 (b)

596 (M⁺ + 1)

TABLE 28 Example No. Structural Formula MS 56 (a)

641 (M⁺ + 1) 56 (b)

641 (M⁺ + 1)

TABLE 29

Example No. R¹ MS 57 (a)

562 (M⁺ + 1) 57 (b)

562 (M⁺ + 1) 58 (a)

604 (M⁺ + 1) 58 (b)

604 (M⁺ + 1) 59 (a)

584 (M⁺ + 1) 59 (b)

584 (M⁺ + 1) 60 (a)

586 (M⁺ + 1) 60 (b)

586 (M⁺ + 1)

TABLE 30

Example No. R¹ MS 61 (a)

602 (M⁺ + 1) 61 (b)

602 (M⁺ + 1) 62 (a)

584 (M⁺ + 1) 62 (b)

584 (M⁺ + 1) 63

588 (M⁺ + 1) 64 (a)

602 (M⁺ + 1) 64 (b)

602 (M⁺ + 1)

TABLE 31

Example No. R¹ MS 65 (a)

649 (M⁺ + 1) 65 (b)

649 (M⁺ + 1)

TABLE 32 Example No. Structural Formula MS 66

646 (M⁺ + 1) 67

657 (M⁺ + 1)

TABLE 33 Example No. Structural Formula MS 68

597 (M⁺ + 1) 69

703 (M⁺ + 1)

TABLE 34 Example No. R¹ MS 70

534 (M⁺ + 1) 71

597 (M⁺ + 1)

TABLE 35

Example No. R¹ MS 72

549 (M⁺ + 1) 73

577 (M⁺ + 1)

TABLE 36 Example No. Structural Formula MS 74

611 (M⁺ + 1)

TABLE 37

Example No. R¹ MS 75

562 (M⁺ + 1) 76

562 (M⁺ + 1) 77

576 (M⁺ + 1) 78

576 (M⁺ + 1)

TABLE 38

Example No. R¹ MS 79 (a)

562 (M⁺ + 1) 79 (b)

562 (M⁺ + 1) 80 (a)

576 (M⁺ + 1) 80 (b)

576 (M⁺ + 1)

TABLE 39

Example No. Structural Formula MS 81

606 (M⁺ + 1) 82

606 (M⁺ + 1) 83

606 (M⁺ + 1) 84

606 (M⁺ + 1)

TABLE 40 Ex- ample No. Structural Formula MS 85

506 (M⁺ + 1) 86

506 (M⁺ + 1)

TABLE 41

Example No. R¹ MS 87

584 (M⁺ + 1) 88

598 (M⁺ + 1) 89

598 (M⁺ + 1) 90

612 (M⁺ + 1)

TABLE 42

Example No. R¹ MS 91

621 (M⁺ + 1) 92

537 (M⁺ + 1) 93

588 (M⁺ + 1) 94

589 (M⁺ + 1) 95

603 (M⁺ + 1) 96

615 (M⁺ + 1) 97 (2)

606 (M⁺ + 1) 98

592 (M⁺ + 1) 99

564 (M⁺ + 1) 100 

606 (M⁺ + 1) 101 

588 (M⁺ + 1)

TABLE 43

Example No. R¹ MS 102 (2)

619 (M⁺ + 1) 103

607 (M⁺ + 1) 104

647 (M⁺ + 1) 105

649 (M⁺ + 1)

TABLE 44 Ex- ample No. Structural Formula MS 106 (2)

493 (M⁺ +1) 107

544 (M⁺ +1)

TABLE 45 Example No. Structural Formula MS 108

619 (M⁺ + 1)

TABLE 46

Example No. R¹ MS 109

507 (M⁺ + 1) 110

558 (M⁺ + 1) 111

559 (M⁺ + 1) 112

624 (M⁺ + 1) 113 (2)

577 (M⁺ + 1) 114 (2)

618 (M⁺ + 1) 115

604 (M⁺ + 1) 116

633 (M⁺ + 1) 117

631 (M⁺ + 1)

TABLE 47 Example No. Structural Formula MS 118 (2)

506 (M⁺ + 1) 119

492 (M⁺ + 1) 120 (a)

612 (M⁺ + 1) 120 (b)

612 (M⁺ + 1)

TABLE 48 Ex- am- ple No. Structural Formula MS 121

590 (M⁺ +1) 122

590 (M⁺ +1) 123

592 (M⁺ +1) 124

592 (M⁺ +1)

TABLE 49 Example No. Structural Formula MS 125

506 (M⁺ + 1) 126

520 (M⁺ + 1) 127

520 (M⁺ + 1) 128

604 (M⁺ + 1)

TABLE 50 Example No. Structural Formula MS 129

548 (M⁺ + 1) 130

576 (M⁺ + 1) 131

614 (M⁺ + 1) 132

548 (M⁺ + 1) 133

590 (M⁺ + 1)

TABLE 51 Example No. Structural Formula MS 134

578 (M⁺ + 1) 135

576 (M⁺ + 1) 136

590 (M⁺ + 1) 137

597 (M⁺ + 1)

TABLE 52

Example No. R¹ MS 138 (a)

614 (M⁺ + 1) 138 (b)

614 (M⁺ + 1)

TABLE 53

Example No. R¹ MS 140

628 (M⁺ + 1) 141

600 (M⁺ + 1) 142

616 (M⁺ + 1) 143

564 (M⁺ + 1) 144

592 (M⁺ + 1) 145

594 (M⁺ + 1) 146

646 (M⁺ + 1) 147

611 (M⁺ + 1)

TABLE 54

Example No. R¹ MS 148

576 (M⁺ + 1) 149

630 (M⁺ + 1)

TABLE 55

Example No. R¹ MS 150

646 (M⁺ + 1) 151

594 (M⁺ + 1) 152

592 (M⁺ + 1) 153

564 (M⁺ + 1) 154

578 (M⁺ + 1) 155

578 (M⁺ + 1) 156

590 (M⁺ + 1) 157

592 (M⁺ + 1)

TABLE 56

Example No. R¹ MS 158

578 (M⁺ + 1) 159

606 (M⁺ + 1) 160

592 (M⁺ + 1) 161

592 (M⁺ + 1) 162

606 (M⁺ + 1) 163

606 (M⁺ + 1) 164

616 (M⁺ + 1) 165

590 (M⁺ + 1)

TABLE 57

Example No. R¹ MS 166

592 (M⁺ + 1) 167

578 (M⁺ + 1) 168

677 (M⁺ + 1) 169

593 (M⁺ + 1) 170

621 (M⁺ + 1) 171

607 (M⁺ + 1) 172

607 (M⁺ + 1) 173

607 (M⁺ + 1)

TABLE 58

Example No. R¹ MS 174

618 (M⁺ + 1) 175

614 (M⁺ + 1) 176

628 (M⁺ + 1) 177

613 (M⁺ + 1) 178

596 (M⁺ + 1) 179

610 (M⁺ + 1)

TABLE 59

Example No. R¹ MS 180

584 (M⁺ + 1) 181

598 (M⁺ + 1) 183

584 (M⁺ + 1) 184

598 (M⁺ + 1) 185

565 (M⁺ + 1) 186

551 (M⁺ + 1) 187

565 (M⁺ + 1)

TABLE 60

Example No. R¹ MS 188

551 (M⁺ + 1) 189

565 (M⁺ + 1) 190

629 (M⁺ + 1) 191

620 (M⁺ + 1) 192

606 (M⁺ + 1)

TABLE 61

Example No. R¹ MS 193

620 (M⁺ + 1) 194

606 (M⁺ + 1) 195

578 (M⁺ + 1) 196

604 (M⁺ + 1)

TABLE 62

Example No. R⁴ MS 197

601 (M⁺ + 1) 198

601 (M⁺ + 1)

TABLE 63

Example No. R¹ MS 199

634 (M⁺ + 1) 200

633 (M⁺ + 1) 201

608 (M⁺ + 1) 202

594 (M⁺ + 1)

TABLE 64

Example No. R¹ MS 203

594 (M⁺ + 1) 204

662 (M⁺ + 1) 205

633 (M⁺ + 1)

TABLE 65

Example No. R¹ MS 206

578 (M⁺ + 1) 207

616 (M⁺ + 1) 208

685 (M⁺ + 1) 209

622 (M⁺ + 1) 210

580 (M⁺ + 1) 211

594 (M⁺ + 1) 212

594 (M⁺ + 1) 213

638 (M⁺ + 1) 214

654 (M⁺ + 1)

TABLE 66

Example No. R¹ MS 215

622 (M⁺ + 1) 216

563 (M⁺ + 1) 217

605 (M⁺ + 1) 218

577 (M⁺ + 1)

TABLE 67

Example No. R¹ MS 219

577 (M⁺ + 1) 220

591 (M⁺ + 1) 221

605 (M⁺ + 1) 222

577 (M⁺ + 1) 223

619 (M⁺ + 1) 224

603 (M⁺ + 1) 225

632 (M⁺ + 1) 226

564 (M⁺ + 1)

TABLE 68

Example No. R¹ MS 227

564 (M⁺ + 1) 228

578 (M⁺ + 1) 229

598 (M⁺ + 1) 230

622 (M⁺ + 1) 231

636 (M⁺ + 1)

TABLE 69

Example No. R¹ n MS 232

1 683 (M⁺ + 1) 233

2 696 (M⁺ + 1) 234

1 681 (M⁺ + 1) 235

1 669 (M⁺ + 1) 236

1 697 (M⁺ + 1) 237

1 683 (M⁺ + 1) 238

1 685 (M⁺ + 1)

TABLE 70

Example No. R¹ MS 239

618 (M⁺ + 1) 240

638 (M⁺ + 1) 241

608 (M⁺ + 1) 242

677 (M⁺ + 1) 243

685 (M⁺ + 1)

TABLE 71

Example No. R¹ MS 244

604 (M⁺ + 1) 245 (a)

569 (M⁺ + 1) 245 (b)

569 (M⁺ + 1) 246

583 (M⁺ + 1)

TABLE 72 Example No. Structural Formula MS 247

660 (M⁺ + 1) 248

549 (M⁺ + 1) 249 (a)

563 (M⁺ + 1) 249 (b)

563 (M⁺ + 1)

TABLE 73 Example No. Structural Formula MS 249 (c)

563 (M⁺ + 1) 250 (2)

534 (M⁺ + 1) 251

578 (M⁺ + 1) 252

534 (M⁺ + 1) 253

578 (M⁺ + 1)

TABLE 74 Example No. Structural Formula MS 254 (2)

565 (M⁺ + 1) 255

565 (M⁺ + 1) 256

551 (M⁺ + 1) 257

537 (M⁺ + 1) 258

567 (M⁺ + 1) 259

581 (M⁺ + 1)

TABLE 75 Example No. Structural Formula MS 260

567 (M⁺ + 1) 261

523 (M⁺ + 1) 262

553 (M⁺ + 1) 263

567 (M⁺ + 1)

TABLE 76 Example No. Structural Formula MS 264

610 (M⁺ + 1) 265

553 (M⁺ + 1) 266

583 (M⁺ + 1) 267

583 (M⁺ + 1) 268

539 (M⁺ + 1)

TABLE 77 Example No. Structural Formula MS 269

569 (M⁺ + 1) 270

597 (M⁺ + 1)

TABLE 78 Example No. Structural Formula MS 271

626 (M⁺ + 1) 272

569 (M⁺ + 1) 273

599 (M⁺ + 1) 274

613 (M⁺ + 1) 275

599 (M⁺ + 1)

TABLE 79 Example No. Structural Formula MS 276

555 (M⁺ + 1) 277

585 (M⁺ + 1) 278

613 (M⁺ + 1)

TABLE 80 Example No. Structural Formula MS 279

604 (M⁺ + 1)

TABLE 81

Example No. R¹ MS 280

564 (M⁺ + 1) 281

592 (M⁺ + 1)

TABLE 82

Example No. R¹ MS 282

550 (M⁺ + 1) 283

564 (M⁺ + 1) 284

564 (M⁺ + 1) 285

578 (M⁺ + 1) 286

578 (M⁺ + 1) 287

603 (M⁺ + 1) 288

591 (M⁺ + 1) 289

605 (M⁺ + 1)

TABLE 83

Example No. R¹ MS 290

605 (M⁺ + 1) 291

619 (M⁺ + 1) 292

645 (M⁺ + 1) 293

552 (M⁺ + 1) 294

617 (M⁺ + 1) 295

646 (M⁺ + 1) 296

663 (M⁺ + 1)

TABLE 84

Example No. R¹ MS 297

706 (M⁺ + 1) 298

795 (M⁺ + 1) 299

668 (M⁺ + 1) 300

566 (M⁺ + 1) 301

605 (M⁺ + 1) 302

619 (M⁺ + 1)

TABLE 85

Example No. R¹ MS 303

619 (M⁺ + 1) 304

633 (M⁺ + 1) 305

659 (M⁺ + 1) 306

617 (M⁺ + 1) 307

631 (M⁺ + 1) 308

660 (M⁺ + 1) 309

677 (M⁺ + 1)

TABLE 86

Example No. R¹ MS 310

564 (M⁺ + 1) 311

564 (M⁺ + 1) 312

603 (M⁺ + 1) 313

737 (M⁺ + 1) 314

605 (M⁺ + 1) 315

648 (M⁺ + 1)

TABLE 87

Example No. R¹ MS 316

619 (M⁺ + 1) 317

647 (M⁺ + 1) 318

578 (M⁺ + 1) 319

574 (M⁺ + 1)

TABLE 88

Example No. R¹ MS 320

607 (M⁺ + 1) 321

621 (M⁺ + 1) 322

621 (M⁺ + 1) 323

594 (M⁺ + 1) 324

608 (M⁺ + 1) 325

624 (M⁺ + 1) 326

580 (M⁺ + 1)

TABLE 89 Example No. Structural Formula MS 327

510 (M⁺ + 1) 328

576 (M⁺ + 1)

TABLE 90 Example No. Structural Formula MS 329

576 (M⁺ + 1) 330

548 (M⁺ + 1)

TABLE 91

Example No. R¹ MS 331

563 (M⁺ + 1) 332

521 (M⁺ + 1) 333

570 (M⁺ + 1) 334

584 (M⁺ + 1) 335 (3)

506 (M⁺ + 1) 336 (2)

521 (M⁺ + 1) 337

578 (M⁺ + 1) 338

604 (M⁺ + 1) 339

631 (M⁺ + 1) 340

602 (M⁺ + 1)

TABLE 92

Example No. R¹ MS 341 (2)

535 (M⁺ + 1) 342

548 (M⁺ + 1) 343

592 (M⁺ + 1) 344

592 (M⁺ + 1) 345

604 (M⁺ + 1) 346

620 (M⁺ + 1) 347

618 (M⁺ + 1) 348

645 (M⁺ + 1) 349

622 (M⁺ + 1)

TABLE 93

Example No. R¹ MS 350

521 (M⁺ + 1) 351

608 (M⁺ + 1) 352

622 (M⁺ + 1)

TABLE 94

Example No. R¹ MS 353

535 (M⁺ + 1) 354

592 (M⁺ + 1) 355

592 (M⁺ + 1) 356

606 (M⁺ + 1) 357

592 (M⁺ + 1) 358

618 (M⁺ + 1) 359

645 (M⁺ + 1)

TABLE 95

Example No. R¹ MS 360

695 (M⁺ + 1) 361

616 (M⁺ + 1) 362

681 (M⁺ + 1) 363

681 (M⁺ + 1) 364

622 (M⁺ + 1) 365

618 (M⁺ + 1)

TABLE 96

Example No. R¹ MS 366

612 (M⁺ + 1) 367

521 (M⁺ + 1)

TABLE 97

Example No. R¹ MS 368

581 (M⁺ + 1) 369

613 (M⁺ + 1) 370

553 (M⁺ − 1) 371

537 (M-I)

TABLE 98

Example No. R¹ MS 372

579 (M⁺ + 1) 373

636 (M⁺ + 1) 374

692 (M⁺ + 1) 375

708 (M⁺ + 1) 376

650 (M⁺ + 1)

TABLE 99

Example No. R¹ MS 377

608 (M⁺ + 1) 378

537 (M⁺ + 1) 379

594 (M⁺ + 1) 380

650 (M⁺ + 1) 381

666 (M⁺ + 1) 382

682 (M⁺ + 1) 383 (3)

611 (M⁺ + 1) 384

627 (M⁺ + 1)

TABLE 100

Example No. Ring B MS 385

472 (M⁺ + 1) 386

512 (M⁺ + 1)

TABLE 101 Example No. Structural Formula MS 387

652 (M⁺ + 1) 388

610 (M⁺ + 1)

TABLE 102

Ex- am- ple No. R¹ MS 389 (2)

676 (M⁺ + 1) 390

648 (M⁺ + 1) 391

691 (M⁺ + 1) 392

705 (M⁺ + 1) 393

705 (M⁺ + 1) 394

705 (M⁺ + 1)

TABLE 103

Ex- ample No. R¹ MS 395

719 (M⁺ +1) 396

733 (M⁺ +1) 397

735 (M⁺ +1) 398

721 (M⁺ +1)

TABLE 104

Ex- ample No. R¹ MS 399

719 (M⁺ + 1) 400

705 (M⁺ + 1) 401

705 (M⁺ + 1) 402

705 (M⁺ + 1)

TABLE 105

Example No. R¹ MS 403

594 (M⁺ + 1) 404

636 (M⁺ + 1) 405

652 (M⁺ + 1) 406

668 (M⁺ + 1)

TABLE 106 Ex- am- ple No. Structural Formula MS 407

565 (M⁺ +1)

TABLE 107

Example No. R¹ MS 408

567 (M⁺ + 1) 409

567 (M⁺ + 1) 410

567 (M⁺ + 1) 411

580 (M⁺ + 1) 412

594 (M⁺ + 1) 413

594 (M⁺ + 1) 414

652 (M⁺ + 1) 415 (2)

610 (M⁺ + 1)

TABLE 108

Ex- am- ple No. R¹ MS 416

624 (M⁺ +1) 417

638 (M⁺ +1) 418

652 (M⁺ +1) 419

652 (M⁺ +1) 420

665 (M⁺ +1) 421

639 (M⁺ +1) 422

737 (M⁺ +1) 423

767 (M⁺ +1)

TABLE 109

Example No. R¹ MS 424

610 (M⁺ + 1) 425

624 (M⁺ + 1) 426

642 (M⁺ + 1) 427

656 (M⁺ + 1)

TABLE 110

Example No. R¹ MS 428

646 (M⁺ + 1) 429

621 (M⁺ + 1) 430

660 (M⁺ + 1) 431

635 (M⁺ + 1)

TABLE 111

Example No. R¹ MS 432

637 (M⁺ + 1) 433

651 (M⁺ + 1) 434

653 (M⁺ + 1) 435

667 (M⁺ + 1)

TABLE 112 Example No. Structural Formula MS 436

624 (M⁺ + 1) 437

596 (M⁺ + 1) 438

562 (M⁺ + 1) 439

548 (M⁺ + 1)

TABLE 113

Example No. R¹ MS 440

493 (M⁺ + 1) 441

580 (M⁺ + 1) 442 (a)

592 (M⁺ + 1) 442 (b)

592 (M⁺ + 1) 443

492 (M⁺ + 1)

TABLE 114

Example No. R¹ MS 444

597 (M⁺ + 1) 445

613 (M⁺ + 1) 446

611 (M⁺ + 1) 447

611 (M⁺ + 1) 448

627 (M⁺ + 1) 449

625 (M⁺ + 1) 450

594 (M⁺ + 1) 451

594 (M⁺ + 1)

TABLE 115

Example No. R¹ MS 452

592 (M⁺ + 1) 453

592 (M⁺ + 1) 454

612 (M⁺ + 1) 455

626 (M⁺ + 1) 456

606 (M⁺ + 1) 457

631 (M⁺ + 1) 458

611 (M⁺ + 1) 459

626 (M⁺ + 1)

TABLE 116

Example No. R¹ MS 460

627 (M⁺ + 1) 461

655 (M⁺ + 1) 462

617 (M⁺ + 1) 463

578 (M⁺ + 1) 464

604 (M⁺ + 1) 465

618 (M⁺ + 1) 466

573 (M⁺ + 1)

TABLE 117 Example No. Structural Formula MS 467

578 (M⁺ + 1) 468

620 (M⁺ + 1) 469

592 (M⁺ + 1)

TABLE 118

Example No. R¹ MS 470

579 (M⁺ + 1) 471

593 (M⁺ + 1) 472

593 (M⁺ + 1) 473

593 (M⁺ + 1) 474

593 (M⁺ + 1) 475

593 (M⁺ + 1) 476

593 (M⁺ + 1)

TABLE 119

Example No. R¹ MS 477

607 (M⁺ + 1) 478

607 (M⁺ + 1) 479

607 (M⁺ + 1) 480

607 (M⁺ + 1)

TABLE 120

Example No. R¹ MS 481 (a)

605 (M⁺ + 1) 481 (b)

605 (M⁺ + 1) 482

619 (M⁺ + 1)

TABLE 121

Example No. R¹ MS 483

619 (M⁺ + 1) 484

633 (M⁺ + 1)

TABLE 122

Example No. R¹ MS 485

619 (M⁺ + 1) 486

633 (M⁺ + 1)

TABLE 123 Example No. Structural Formula MS 487

580 (M⁺ + 1)

TABLE 124 Example No. Structural Formula MS 488 (2)

610 (M⁺ + 1)

TABLE 125 Reference Example No. Structural Formula MS 1

450 (M⁺ + 1) 2

342 (M⁺ + 1) 3

388 (M⁺ + 1) 4

254 (M⁺ + 1) 5

254 (M⁺ + 1)

TABLE 126 Refer- ence Ex- ample No. Structural Formula MS  6

505 (M⁺ + 1)  7

491 (M⁺ + 1)  8

505 (M⁺ + 1)  9

505 (M⁺ + 1) 10

505 (M⁺ + 1) 11 (1)

491 (M⁺ + 1)

TABLE 127 Ref- er- ence Ex- am- ple No. Structural Formula MS 11 (2)

505 (M⁺ +1) 12 (a)

399 (M⁺ +1) 12 (b)

399 (M⁺ +1)

TABLE 128 Ref- er- ence Ex- am- ple No. Structural Formula MS 13 (a)

413 (M⁺ +1) 13 (b)

413 (M⁺ +1)

TABLE 129 Reference Example No. Structural Formula MS 14

265 (M⁺ + 1) 15

265 (M⁺ + 1)

TABLE 130 Reference Example No. Structural Formula MS 16

279 (M⁺ + 1) 17

279 (M⁺ + 1)

TABLE 131 Reference Example No. Structural Formula MS 18 (a)

443 (M⁺ + 1) 18 (b)

443 (M⁺ + 1)

TABLE 132 Reference Example No. Structural Formula MS 19

309 (M⁺ + 1) 20

173 (M⁺ + 1) 21

186 (M⁺ + 1) 22

260 (M⁺ + 1) 23

266 (M⁺ + 1)

TABLE 133 Refer- ence Ex- ample No. Structural Formula MS 24 (2)

266 (M⁺ + 1) 25 (3)

535 (M⁺ + 1) 26 (5)

297 (M⁺ + 1) 27

288 (M⁺ + 1) 28 (2)

396 (M⁺ + 1)

TABLE 134 Reference Example No. Structural Formula MS 29 (5)

313 (M⁺ + 1) 30 (5)

265 (M⁺ + 1) 31 (2)

353 (M⁺ + 1) 32

306 (M⁺ + 1) 33

210 (M⁺ + 1) 34

319 (M⁺ + 1)

TABLE 135 Reference Example No. Structural Formula MS 35

272 (M⁺ + 1) 36 (4)

279 (M⁺ + 1) 37 (4)

283 (M⁺ + 1)

TABLE 136 Reference Example No. Structural Formula MS 38

210 (M⁺ + 1) 39

288 (M⁺ + 1)

INDUSTRIAL APPLICABILITY

The compound of the present invention of a salt thereof has an excellenttachykinin receptor antagonistic action. Further, the compound of thepresent invention or a salt thereof is excellent in terms of safety,absorption, transportability into brain, metabolic stability,concentration in blood and sustainability, so that it has excellentpharmaceutical effects.

1.-19. (canceled)
 20. A piperidine compound. represented by the formulas[I]:

Wherein Ring A represents an optionally substituted benzene ring, Ring Brepresents an optionally substituted benzene ring, R¹ represents,substituted hydroxyl group, R² represents hydrogen atom, an optionallysubstituted hydroxyl group, an optionally substituted amino group, anoptionally substituted alkyl group, a substituted carbonyl group or ahalogen atom, Z represents oxygen atom or a group represented by—N(R³)—, wherein R³ represents hydrogen atom or an optionallysubstituted alkyl group and R⁴ represents hydrogen atom or an optionallysubstituted alkyl group, or a pharmaceutically acceptable salt thereof.21. The compound according to claim 20, wherein R¹ is a substitutedcarbonyloxy group, a substituted sulfinyloxy group, a substitutedsulfonyloxy group, or an optionally substituted alkyloxy group.
 22. Thecompound according to claim 20 wherein R¹ is an optionally substitutedalkylcarbonyloxy group, an optionally substituted alkoxycarbonyloxygroup, an optionally substituted aminocarbonyloxy group, an optionallysubstituted monocyclic heterocyclic carbonyloxy group wherein themonocyclic heterocyclic group has 1 to 2 atom(s) selected from nitrogenatom and oxygen atom as a hetero atom, a substituted sulfinyloxy group,a substituted sulfonyloxy group, an optionally substitutedhydoroxyalkyloxy group, dialkylaminoalkyloxy group, or an optionallysubstituted monocyclic heterocyclic alkyloxy group wherein themonocyclic heterocyclic group has 1 to 2 atom(s) selected from nitrogenatom and oxygen atom as hereto atom.
 23. The compound according to claim20, wherein R¹ is a hydroxyalkylcarbonyloxy group, analkoxyalkoxycarbonyloxy group, a hydroxyalkoxycarbonyloxy group, ahalogenoalkoxycarbonyloxy group, a halogenoalkylaminocarbonyloxy group,a dialkylaminoalkylaminocarbonyloxy group, apiperidinylalkylaminocarbonyloxy group, amorpholinoalkylaminocarbonyloxy group, a carboxylalkylaminocarbonyloxygroup, a morpholinocarbonylalkylaminocarbonyloxy group, adialkylaminocarbonylalkylaminocarbonyloxy group, analkanoylaminoalkylaminocarbonyloxy group, analkylthioalkylaminocarbonyloxy group, analkylsulfonylalkylaminocarbonyloxy group, analkanoyloxyalkylaminocarbonyloxy group, hydroxyalkylaminocarbonyloxygroup, a hydroxyalkanoylpiperidinylaminocarbonyloxy group, analkoxyalkanoylpeperidinylaminocarhonyloxy group, adialkylaminosulfonylaminocarbonyloxy group, morpholinocarbonyloxy group,a piperazinylcarbonyloxy group, an imidazolylcarbonyloxy group,thiomorpholinocarbonyloxy group, piperidinocarbonyloxy group, afurylcarbonyloxy group, a tetrahydrothiazolinylcarbonyloxy group, anirrolidinylcarbonyloxy group, an alkylsulfinyloxy group, athienylsulfinyloxy group, an alkylsulfonyloxy group, athienylsulfinyloxy group, an alkoxyalkyloxy group, analkylsulfonyloxyalkoxy group, a tetrahydropyranyloxyalkoxy group,dialkylaminoalkyloxy group, a pyridylalkoxy group, a piperidinylalkoxygroup, morholinoalkoxy group, an isoxazolylalkoxy group, atriazolylalkoxy group, a tetrazolylalkoxy group, or a pirrolidinylalkoxygroup.
 24. The compound according to claim 20, wherein Ring A is abenzene ring of the formula:

and Ring B is a benzene ring of the formula:

Wherein A¹ is an alkyl group, hydrogen atom, a halogen atom or an alkoxygroup, A² is hydrogen atom or a halogen atom, A³ is hydrogen atom, B¹ isa trihalogenoalkyl group, a halogen atom or an alkyl group, B² is atrihalogenoalkyl group, a halogen atom or an alkyl group, B³ is hydrogenatom, R¹ an alkoxy group optionally substituted by hydroxyl group, analkylsulfonyloxy group, a tetrahydropyranyloxy group, a dialkylaminogroup, pyridyl group, a triazolyl group, a tetrazolyl group optionallysubstituted by an alkyl group, piperidino group, morpholino group,pyrrolidino group or an alkoxy group; morpholinocarbonyloxy group; alkylpiperazinocarbonyloxy group; imidazolylcarbonyloxy group;peridinoalkylaminocarbonyloxy group; morpholinoalkylaminocarbonyloxygroup; an alkylaminocarbonyloxy group wherein the alkyl moiety thereofis optionally substituted by hydroxyl group, a morpholinocarbonyl group,a dialkylaminocarbonyl group, an alkylaminocarbonyl group analkanoylamino group, an alkylthio group, an alkoxy group, analkylsulfonyl group, an alkanoyloxy group or a carboxyl group;dialkylaminoalkylaminocarbonyloxy group; a piperidinocarbonyloxy groupsubstituted by hydroxyl group, an alkoxycarbonyl group, a carboxylgroup, a hydroxyalkylaminocarbonyl group, an alkoxyalkylaminocarbonylgroup, an alkylthioalkylaminocarbonyl group, analkylsulfinylalkylaminocarbonyl group, analkylsulfonylalkylaminocarbonyl group or hydroxyalkyl group;dialkylaminocarbonyloxy group optionally substituted by hydroxyl group;a piperidinylaminocarbonyloxy group substituted by a hydroxyalkanoylgroup or an alkoxyalkanoyl group; a thiomorpholinocarbonyloxy groupwherein the sulfur atom is optionally substituted by an oxo group;oxoyrrolidinylcarbonyloxy group; oxotetrahydrothiazolinylcarbonyloxygroup; dialkylaminosulfonylaminocarbonyloxy group; a carboxyl group; R²is hydrogen atom, Z is an oxygen atom or a group represented by —N(R³)—,R³ is an alkyl group optionally substituted by hydroxyl group or analkanoyl group, R⁴ is hydrogen atom or an alkyl group optionallysubstituted by hydroxyl group.
 25. A compound selected from thefollowing (A) to (I), (A)(2R,4S)-1-{N-(3,5-bistrifluoromethylbenzyl)-N-methyl}-aminocarbonyl-2-(4fluoro-2-methylphenyl)-4-(2-hydroxyethoxy)-piperidine,(B)(2R,4S)-1-[N-{1-(R)-(3,5-bistrifluoromethylphenyl)ethyll-N-methyl]aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-{2-(2-tetrahydropyranyloxy)ethoxy}piperidine, (C)(2R,4S)-1-[N-{1-(S)-(3,5-bistrifluoromethylphenyl)ethyl}-N-methyl]aminocarbonyl-2-)4-fluoro-2-methylphenyl)-4-methoxy-acetylaminopiperidine,(D)(2R,4S)-1-[N-{1-(S)-(3,5-bistrifluoroethylphenyl)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-methoxy-carbonylaminopiperidine,(E)(2R,4S)-1-[N-{1-(S)-(3,5-bistrifluoroethylphenyl)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-(2-hydroxyethoxy)piperidine,(F)(2R,4S)-1-[N-{1-(R)-(3,5-bistrifiluoromethylphenyl)ethyl}-n-methyl]aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-(3-hydroxypropoxy)piperidine,(G)(2R,4S)-1-{N-(3,5-bistrifluoromethylbenzyl)-N-methyl}-aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-(2-hydroxyethyl-aminocarbonyloxy)piperidine,(H)(2R,4S)-1-[N-{l-(R)-3,5-bistrifluoromethylphenyl)ethyl}-N-methyl]aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-(2-hydroxyethylaminocarbonyloxy)piperidine,or (I)(2R,4S)-I-{N-(3,5,-bistrifluoroethylbenzyl)-N-methyl}-aminocarbonyl-2-(4-fluoro-2-methylphenyl)-4-(1-oxothio-morpholinocarbonyloxy)piperidine.26. A method for preparing a piperidine compound of the formula [I′]:

Wherein Ring A represents an optionally substituted benzene ring, Ring Brepresents an optionally substituted benzene ring, R¹ represents anoptionally substituted hydroxyl group, R² represents hydrogen atom, anoptionally substituted hydroxyl group, an optionally substituted aminogroup, an optionally substituted alkyl group, a substituted carbonylgroup or a halogen atom, R³ represents hydrogen atom or an optionallysubstituted alkyl group and R⁴ represents hydrogen atom or an optionallysubstituted alkyl group, or a pharmaceutically acceptable salt thereof,comprising reacting a compound of the formula [II]:

Wherein Ring A, R¹ and R² have the same meanings as defined above, witha compound of the formula [III ]:

Wherein Ring B, and R⁴ have the same meanings as defined above, in thepresence of a urea bond forming agent, and if desired, converting into apharmaceutically acceptable salt thereof.
 27. A method for preparing apiperidine compound of the formula [I″}:

Wherein Ring A represents an optionally substituted benzene ring, Ring Brepresents an optionally substituted benzene ring, R¹ represents anoptionally substituted hydroxyl group, R² represents hydrogen atom, anoptionally substituted hydroxyl group, an optionally substituted aminogroup, an optionally substituted alkyl group, a substituted carbonylgroup or a halogen atom, R³ represents hydrogen atom or an optionallysubstituted alkyl group and R⁴ represents hydrogen atom or an optionallysubstituted alkyl group, or a pharmaceutically acceptable salt thereof,comprising reacting a compound of the formula [II]:

Wherein Ring A, R¹ and R² have the same meaning as defined above, with acompound of the formula [III′]:

Wherein Ring B, R³ and R⁴ have the same meanings as defined above, inthe presence of a urea bond forming agent, and if desired, convertinginto a pharmaceutically acceptable salt thereof.
 28. A pharmaceuticalcomposition comprising the compound according to any one of claims 20 to26, in a clinically effective dose and a pharmaceutically acceptablecarrier.
 29. A method for treating and preventing a disease selectedfrom inflammation, allergic diseases, pain, migraine, neuralgia,itchiness, cough, central nervous system diseases, digestive organsdisease nausea, emesis, urinary disorder, circulatory disease and immunedisorder, comprising administering the compound according to any one ofclaims 20 to 26 in a clinically effective dose to a mammal.
 30. Themethod according to claim 29, wherein the disease is urinary disorder.